Method of treating with CYP3a4 substrate drug

Abstract

To provide methods of treating a patient with a CYP3A4 substrate drug, whereby the patient is to be treated with posaconazole.SOLUTION: In some embodiments, a patient is to be treated with the CYP3A4 substrate drug once the safety of posaconazole treatment is confirmed, before which the patient has been made to wait at least two days after the stopping of the posaconazole treatment. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 2-42 days after the stopping of posaconazole administration. In some embodiments, the patient is treated at a reduced dose of the CYP3A4 substrate drug for about 2-42 days.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 16 / 036,678, filed July 16, 2018, the entire contents of which are incorporated herein by reference.

[0002] Posaconazole, also known as Noxafil or Posanol, is indicated for the prevention of invasive Aspergillus and Candida infections in patients at high risk due to severe immunodeficiency, such as those with graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT) and those with hematologic malignancies experiencing prolonged chemotherapy-induced neutropenia, as well as for the treatment of oropharyngeal candidiasis (OPC), including oropharyngeal candidiasis (rOPC) refractory to itraconazole and / or fluconazole, invasive aspergillosis, and zygomycosis. Posaconazole is also used "off-label" for the treatment of allergic bronchopulmonary aspergillosis, the prevention and treatment of recurrent esophageal candidiasis secondary to HIV infection, Fusarium infections, and chronic or cavitary necrotizing pulmonary aspergillosis.

[0003] Posaconazole is a potent inhibitor of the CYP3A4 enzyme, a member of the cytochrome P450 family of oxidative enzymes present in the liver. Cytochrome P450 enzymes, such as CYP3A4, oxidize small organic molecules in the body, such as toxins and certain drugs, resulting in their inactivation and / or degradation. Organic molecules in the body (e.g., drugs) that are primarily oxidized by a particular enzyme are called "substrates" for the associated enzyme. In other words, drugs that are primarily oxidized by the CYP3A4 enzyme are "CYP3A4 substrate drugs."

[0004]

[0004] The Noxafil label is intended to protect against certain drugs metabolized by CYP3A4, such as sirolimus. The label specifically contraindicates coadministration of posaconazole with other drugs metabolized by CYP3A4, including CYP3A4 substrates such as pimozide and quinidine, HMG-CoA reductase inhibitors metabolized primarily via CYP3A4, and ergot alkaloids. It also indicates that dose adjustments should be considered when posaconazole is coadministered with other drugs metabolized by CYP3A4, including tacrolimus, cyclosporine, vinca alkaloids such as vincristine and vinblastine, and calcium channel blockers such as verapamil, diltiazem, nifedipine, nicardipine, and felodipine. However, the label for Noxafil does not recommend coadministration of posaconazole with other CYP3A4 substrates. Although specific drug-drug interactions associated with coadministration have been identified, none have been reported regarding the administration of CYP3A4 substrate drugs after discontinuation of posaconazole. Summary of the Invention [Problem to be solved by the invention]

[0005]

[0005] The inventors of the present invention have discovered that in order to prevent or reduce the occurrence of dangerous side effects caused by CYP3A4 substrate drugs, it is necessary to postpone the administration of CYP3A4 substrate drugs after discontinuing administration of posaconazole, or in some cases, adjust the dose of the CYP3A4 substrate drug at specified time intervals. [Means for solving the problem]

[0006]

[0006] The present disclosure provides methods for treating patients who have previously received posaconazole in a therapeutically effective regimen with a CYP3A4 substrate drug that is contraindicated for co-administration with a strong CYP3A4 inhibitor.

[0007]

[0007] The applicant has found that although most CYP3A4 substrate drugs are prohibited from co-administration with strong CYP3A4 inhibitors such as posaconazole, the co-administration of posaconazole with other drugs is not sufficient to prevent the occurrence of side effects immediately after discontinuing posaconazole treatment. Applicant has found that if a CYP3A4 substrate drug is subsequently administered to a patient, safety cannot be guaranteed. Furthermore, Applicant has found that if posaconazole accumulates in the body of a patient, particularly in the specific patient population described herein, administering a CYP3A4 substrate drug too early after discontinuing the posaconazole regimen may cause serious and potentially life-threatening side effects. Therefore, for CYP3A4 substrate drugs, particularly CYP3A4 substrate drugs that are prohibited from co-administration with strong CYP3A4 inhibitors (including, but not limited to, posaconazole), a withdrawal or delay period of about 2 to 42 days (e.g., about 2 to 21 days) should be allowed between the discontinuation of posaconazole administration and the initiation of administration of the CYP3A4 substrate drug to avoid or reduce the occurrence of side effects attributable to the administration of the CYP3A4 substrate drug. Alternatively, according to the applicant, in some embodiments, instead of postponing administration of the CYP3A4 substrate drug after discontinuing administration of posaconazole, the safety of the patient can be ensured by administering a reduced dose of the CYP3A4 substrate drug (lower than the recommended dose of the CYP3A4 substrate drug) for a certain period of time (approximately 2 to 42 days (e.g., approximately 2 to 21 days)) after discontinuing the posaconazole regimen, and then increasing the dose of the CYP3A4 substrate drug to the recommended level.

[0008] In certain embodiments, the disclosed methods of postponing treatment with a CYP3A4 substrate drug or reducing the dose of a CYP3A4 substrate drug for about 2 to 42 days (e.g., about 2 to 21 days) after discontinuation of posaconazole are intended for normal patients, e.g., non-obese normal CYP3A4 metabolizers. In certain embodiments, the disclosed methods of postponing treatment with a CYP3A4 substrate drug or reducing the dose of a CYP3A4 substrate drug for about 2 to 42 days (e.g., about 2 to 21 days) after discontinuation of posaconazole are intended for patients with the specific physiological characteristics described herein. Because patients may be exposed to larger amounts of CYP3A4 substrate drug after discontinuation of posaconazole than is known, a longer "drug holiday" period or longer reduced-dose treatment with a CYP3A4 substrate drug after discontinuation of posaconazole may be required prior to initiation of treatment with the CYP3A4 substrate drug to avoid or reduce the occurrence of adverse effects associated with treatment with the CYP3A4 substrate drug. More specifically, applicants have discovered that patients with certain physiological characteristics will experience greater than expected exposure to administered CYP3A4 substrate drugs after discontinuation of posaconazole than "normal" patients (e.g., patients who are otherwise identical but do not have the specific physiological characteristics described herein). For example, patients with a BMI in the "normal" range (approximately 18.5-24.9) may have significantly reduced excretion of CYP3A4 substrate drugs, and these patients are referred to as CYP3A4 poor or intermediate metabolizers. Thus, as described herein, the inventors have discovered that for certain patient populations, a longer drug-free period between the discontinuation of posaconazole and the initiation of treatment with a CYP3A4 substrate drug may be required, or a reduced dose of the CYP3A4 substrate drug may be administered for a specified period after discontinuation of posaconazole treatment.

[0009] In various embodiments, the disclosure provides methods for treating a patient in which initial treatment with a CYP3A4 substrate drug is postponed until about 2 to 42 days (e.g., 2 to 21 days) after discontinuing posaconazole administration. In embodiments, the CYP3A4 substrate drug is a drug that is contraindicated in combination with a strong CYP3A4 inhibitor, such as, but not limited to, posaconazole. Accordingly, in various embodiments, the disclosure provides methods for treating a patient who has previously been treated with multiple doses of posaconazole with a CYP3A4 substrate drug that is contraindicated in combination with a strong CYP3A4 inhibitor, the methods comprising administering or prescribing to the patient initial treatment with a stable dose of the CYP3A4 substrate drug for at least 2 to 42 days (e.g., 2 to 21 days) after discontinuing posaconazole treatment.

[0010] In various embodiments, the present disclosure provides a method for treating posaconazole-induced steroid deficiency by administering about 50% or less of the reference dose of a CYP3A4 substrate drug for about 2 to 42 days (e.g., 2 to 21 days) after discontinuing posaconazole treatment.

[0010] Methods are provided for initially treating or prescribing to initiate initial treatment for a patient with a CYP3A4 substrate drug at a dose of about 50% or less of the baseline dose. Accordingly, in various embodiments, the methods include treating or prescribing to initiate treatment for a patient in need thereof with a therapeutically effective amount of a CYP3A4 substrate drug that is contraindicated for concomitant use with a strong CYP3A4 inhibitor. In some embodiments, the patient has previously received posaconazole treatment. In some embodiments, the patient is treated or prescribed treatment with a CYP3A4 substrate drug at a dose of about 50% or less of the baseline dose for about 2 to 42 days (e.g., 2 to 21 days) after discontinuing the posaconazole regimen.

[0011] In some embodiments, after the delay described herein (e.g., at least 2 days, including 242 days), the CYP3A substrate drug is administered with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, the CYP3A4 substrate drug is administered in step (d) as soon as at least one of the AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substrate drug no longer exceeds a maximum level at which the benefits of treating the patient outweigh the risks of high exposure to the CYP3A4 substrate drug. In some embodiments, the maximum level at which the benefits of treating the patient outweigh the risks of high exposure to the CYP3A4 substrate drug is a target safe level set forth in Table A. In some embodiments, the CYP3A4 substrate drug is administered to achieve an AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substrate drug that is above baseline but does not exceed the target safe level set forth in Table A for the CYP3A4 substrate drug. In some embodiments, the CYP3A4 substrate drug is administered to achieve an AUC or Cmax of the CYP3A4 substrate drug that is at least about 105% of the predicted AUC or Cmax for the day the CYP3A4 substrate drug is administered. In some embodiments, the CYP3A4 substrate drug is administered to achieve an AUC or Cmax of the CYP3A4 substrate drug that is at least about 105% of the predicted AUC or Cmax for the day the CYP3A4 substrate drug is administered, but does not exceed the target safety level set forth for the CYP3A4 substrate drug in Table A. In some embodiments, the CYP3A4 substrate drug is administered to achieve a GMR AUC or GMR Cmax of the CYP3A4 substrate drug that is at least about 1.05-fold the predicted AUC or Cmax. In some embodiments, the CYP3A4 substrate drug is administered to achieve a GMR AUC or GMR Cmax of the CYP3A4 substrate drug that is at least about 1.05-fold the expected AUC or Cmax, but does not exceed the target safety level set forth in Table A for the CYP3A4 substrate drug.

[0012]

[0012] In some embodiments, the CYP3A4 substrate drug is selected from the group consisting of abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole, ivacaftor / tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, elbasvir / grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib and vemurafenib.

[0013] In some embodiments, the method is for the treatment of non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age or older; recurrent follicular lymphoma (FL) in adults who have received at least two prior systemic therapies; adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies in combination with binimetinib; unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test, significant Treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), characterized by low sexual desire that is not due to a coexisting medical or psychiatric condition that causes significant distress or interpersonal difficulties; relationship problems; or the effects of drugs or other medicinal substances; reducing the risk of hospitalization due to worsening heart failure in patients with stable, symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less, with a resting heart rate of 70 beats per minute or greater in sinus rhythm, taking a maximally tolerated beta-blocker, or in whom beta-blocker use is contraindicated; adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent; adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy or who are not candidates for surgery or radiation therapy; unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; Erdheim-Chester disease with a V600 mutation; non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older; adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies; adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; BRAF as detected by an FDA-approved test Treatment in combination with binimetinib in patients with unresectable or metastatic melanoma harboring a V600E or V600K mutation; a coexisting medical or psychiatric condition causing significant distress or interpersonal difficulties; relationship problems; or premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire not due to the effects of drugs or other medicinal substances;Reducing the risk of hospitalization due to worsening heart failure in patients with stable, symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less who are in sinus rhythm with a resting heart rate of 70 beats per minute or greater and are taking a maximum tolerated dose of a beta-blocker or who have a contraindication to beta-blocker use; adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; treatment of patients with multiple myeloma who have received at least two prior regimens containing bortezomib and an immunomodulatory agent, or adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy, or who are not candidates for surgery or radiation therapy; BRAF as detected by an FDA-approved test; The present invention provides a method for treating a patient having a disease or condition selected from the group consisting of: a patient having unresectable or metastatic melanoma with a V600E mutation; and a patient having Erdheim-Chester disease with a BRAF V600 mutation.

[0014] In various embodiments, the present disclosure provides a method for the treatment of schizophrenia in adults and adolescents (ages 13-17), depressive episodes associated with bipolar disorder type 1 (bipolar depression) in adult and pediatric patients (ages 10-17) (either as monotherapy or adjunctive therapy with lithium or valproate), moderate bipolar depression, severe bipolar depression, and severe bipolar depression with acute suicidal ideation and behavior (ASIB), chronic angina, cystic fibrosis in patients 6 years of age and older who are homozygous for the F508del mutation in the CFTR gene, chronic lymphocytic leukemia in patients with a chromosome 17 short arm deletion who have received at least one prior therapy, and in patients who have previously received an anthracycline. Unresectable or metastatic liposarcoma or leiomyosarcoma in patients receiving regimens containing HER2, hormone receptor (HR)-positive advanced or metastatic breast cancer in postmenopausal women, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, negative advanced or metastatic breast cancer (in combination with aromatase inhibitors in postmenopausal women), Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients on dialysis with chronic kidney disease (CKD), high calcium in patients with primary hyperparathyroidism or parathyroid carcinoma who are recommended for parathyroidectomy based on serum calcium levels but cannot undergo parathyroidectomy. Calciumemia, hallucinations and delusions due to Parkinson's disease psychosis, schizophrenia, acute manic or mixed episodes associated with bipolar I disorder, chronic hepatitis C (CHC) infection (as a component of a combination antiviral treatment regimen with pegylated interferon alpha and ribavirin for HCV genotype 1-infected subjects with compensated liver disease), postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+BC) (e.g., in combination with exemestane after treatment failure with letrozole or anastrozole), advanced neuroendocrine tumors of pancreatic origin (PNET), unresectable and locally advanced or metastatic advanced well-differentiated non-functioning neuroendocrine tumors (NET) of gastrointestinal (GI) or pulmonary origin, advanced renal cell carcinoma (RCC) (e.g., after failure of treatment with sunitinib or sorafenib), renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, TSC in patients with subependymal giant cell astrocytoma (SEGA) requiring treatment intervention but not candidates for surgical resection, type 2 diabetes in adults (as an adjunct to diet and exercise therapy to improve glycemic control), major depressive disorder (MDD), acute coronary syndrome (ACS) thrombotic cardiovascular events (e.g., cardiovascular death, myocardial infarction, or stroke) in patients with non-valvular atrial fibrillation; stroke and systemic embolism in patients with non-valvular atrial fibrillation; deep vein thrombosis (DVT) with the potential to precipitate pulmonary embolism (PE) in patients undergoing hip or knee replacement surgery; DVT, PE, recurrent DVT and PE associated with initial treatment; moderate to severe active rheumatoid arthritis in patients with an inadequate response or resistance to methotrexate; acute migraine with or without aura; chronic rheumatoid arthritis in newly diagnosed patients or patients with resistance or intolerance to prior treatment including imatinib. Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in phase and accelerated phase, atrial fibrillation (AF) in patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or are being cardioverted, asthma in patients aged 4 years and older, obstructive pulmonary disease and reduction of exacerbations in patients with chronic obstructive pulmonary disease, erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHO classification group 1) (for the purpose of improving exercise capacity), gout flares, familial Mediterranean fever, antiretroviral therapy, anxiety disorders, panic disorders, seizures, insomnia, hypertension, cardiovascular disease,Hyperlipidemia, primary renal cell carcinoma, advanced primary liver cancer, radioactive iodine-resistant advanced thyroid cancer, cancers such as renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumors, mantle cell lymphoma in patients who have received at least one prior treatment, chronic lymphocytic leukemia / small lymphocytic lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma with deletion of the short arm of chromosome 17, Waldenstrom macroglobulinemia, marginal zone lymphoma in patients who require systemic treatment and have received at least one anti-CD20 treatment, and BRAF Unresectable or metastatic melanoma with V600E or V600K mutations, allergy, transplant, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, treatment of clinically significant polycythemia and euvolemic hyponatremia, including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of high-dose cisplatin-containing highly emetogenic cancer chemotherapy (HEC), prevention of delayed nausea and vomiting associated with initial and repeated courses of moderately emetogenic cancer chemotherapy (MEC), overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, first-line treatment after progression in patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. metastatic non-small cell lung cancer (NSCLC) receiving treatment, maintenance treatment, or second-line or higher treatment; locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine; HER-2 positive metastatic breast cancer previously treated with trastuzumab and a taxane, either separately or in combination, in patients who have previously been treated for metastatic disease or who have developed disease recurrence during or within 6 months of completing adjuvant therapy; adult Ph+ chronic myeloid leukemia (CML) in chronic, accelerated, or acute phase with resistance or intolerance to previous therapy; gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate; advanced renal cell carcinoma (RCC); advanced well-differentiated pancreatic neuroendocrine tumor (pNET) in patients with unresectable, locally advanced, or metastatic disease; CCR5-tropic HIV-1 infection in patients 2 years of age or older weighing at least 10 kg, in combination with other antiretrovirals;progressive renal cell carcinoma, Advanced soft tissue sarcoma who have received previous chemotherapy, manic and mixed episodes associated with bipolar disorder type 1, major depressive disorder, hyperirritability associated with autistic disorder, Tourette's disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one prior systemic therapy, improving glycemic control in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with dapagliflozin or already treated with dapagliflozin and saxagliptin, advanced metastatic medullary thyroid carcinoma (MTC), and those who have not received prior antiangiogenic therapy. Advanced renal cell carcinoma (RCC) who have received prior chemotherapy; adult chronic, accelerated, or acute phase chronic myeloid leukemia (CML) or Ph+ALL for which other tyrosine kinase inhibitor (TKI) therapy is not indicated; adult T315I-positive CML (chronic, accelerated, or acute phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); invasive aspergillosis; invasive mucormycosis; and low-density lipoprotein cholesterol (LDL-C) and total cholesterol in patients with homozygous familial hypercholesterolemia (HoFH). (TC), apolipoprotein B (apoB), and non-high-density lipoprotein cholesterol (non-HDL-C); adult schizophrenia; hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with aromatase inhibitors as initial endocrine therapy in postmenopausal women or fulvestrant in women with disease progression after endocrine therapy; major depressive disorder (MDD); suppression of motor and vocal tics in patients with Tourette's syndrome who have not responded adequately to standard treatment; lenalidomide Treatment of multiple myeloma in patients who have received at least two prior therapies, including steroid and proteasome inhibitors, and have shown disease progression within 60 days of completing the last treatment; non-small cell lung cancer (NSCLC) with no disease progression after four cycles of platinum-based first-line chemotherapy; locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen; locally advanced, unresectable, or metastatic pancreatic cancer; overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency; advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib;In combination with fulvestrant as monotherapy for the treatment of adult patients with tuberous sclerosis (TS)-associated subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, tuberous sclerosis complex, HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy, clinical and / or in vitro, who require procedural intervention but are not candidates for curative surgical resection, or who have disease progression after endocrine therapy and prior chemotherapy in the metastatic setting. Based on the data from the ivacaftor assay, cystic fibrosis (CF) in patients aged 2 years and older with a single mutation in the CFTR gene that responds to ivacaftor; germline BRCA-mutated advanced ovarian cancer in adult patients who have been treated with three or more prior lines of chemotherapy and are suspected of having adverse or harmful outcomes; intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis; patients with polycythemia vera who have had an inadequate response to or are intolerant to hydroxyurea; and major depression. As adjunctive therapy to antidepressants for the treatment of myelodysplastic syndrome (MDD), schizophrenia, cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation or have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene who respond to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence, and who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. patients with metastatic colorectal cancer (CRC) who have been previously treated with imatinib mesylate and sunitinib malate; patients with locally advanced, unresectable, or metastatic gastrointestinal stromal tumors (GIST); patients with hepatocellular carcinoma (HCC) who have previously been treated with sorafenib; patients with chronic HCV genotype 1 or 3 infection with sofosbuvir, with or without ribavirin; patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1 positive as detected by an FDA-approved test; patients with chronic pain related to their previous cancer or its treatment and who have frequent (e.g.,patients with chronic non-cancer pain, including those not requiring weekly opioid dose escalation, opioid-induced constipation (OIC) in adult patients with unresectable or metastatic melanoma in patients with a BRAF V600E mutation as detected by an FDA-approved test; unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation as detected by an FDA-approved test, in combination with trametinib; melanoma in patients with a BRAF V600E or V600K mutation as detected by an FDA-approved test and lymph node metastasis after complete resection; metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation as detected by an FDA-approved test; BRAF for which there are no satisfactory local treatment options locally advanced or metastatic anaplastic thyroid carcinoma (ATC) in patients with a V600E mutation; treatment of chronic HCV genotype 1 or 4 infection in adults with or without ribavirin; treatment of patients with non-metastatic castration-resistant prostate cancer; treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib; treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age or older; and treatment of recurrent follicular lymphoma (FL) who have received at least two prior systemic therapies. treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; treatment in combination with binimetinib in patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test; treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that causes significant distress or interpersonal difficulties and is not due to a coexisting medical or psychiatric condition; relationship problems; or the effects of drugs or other medicinal substances; treatment of patients with stable disease with a left ventricular ejection fraction of 35% or less, who have a resting heart rate of 70 beats per minute or greater, are taking a maximally tolerated dose of a beta-blocker, or who have a contraindication to beta-blocker use. reducing the risk of hospitalization due to worsening heart failure in patients with symptomatic chronic heart failure; treating adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; treating patients with multiple myeloma who have received at least two prior regimens comprising bortezomib and an immunomodulatory agent; treating adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy or who are not candidates for surgery or radiation therapy; treating patients with unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; and treating patients with Erdheim-Chester disease with a BRAF V600 mutation.

[0015] In some embodiments, the method involves treating a disease or condition with a CYP3A4 substrate drug that is contraindicated for use with a strong CYP3A4 inhibitor, but the patient is required to be treated with a strong CYP3A4 inhibitor (i.e., posaconazole). In some embodiments, the method involves (a) postponing initial treatment with a CYP3A4 substrate drug for at least about 2-42 days after discontinuing administration of posaconazole, and then (b) administering or prescribing initial treatment with a CYP3A4 substrate drug. In other embodiments, the method involves (a) postponing initial treatment with a CYP3A4 substrate drug for at least about 2-21 days after discontinuing administration of the posaconazole regimen, and then (b) administering or prescribing initial treatment with a CYP3A4 substrate drug at a dose of no more than about 50% of the reference dose for at least about 2-42 days after discontinuing administration of posaconazole. [Brief explanation of the drawings]

[0016] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0016] Mean (± standard error) plasma posaconazole concentrations in normal weight and obese subjects during and after cessation of posaconazole administration are shown. For kinetic analysis, see Table 2. [Figure 2A]

[0017] Figure 2 shows mean plasma lurasidone concentrations in normal weight (Figures 2A and 2B) and obese (Figures 2C and 2D) subjects. Figure 2A shows the 72-hour study period on a logarithmic concentration axis (days 20 and 26 data not shown). [Figure 2B] Mean plasma lurasidone concentrations in normal weight subjects (Figures 2A and 2B) are shown. Figure 2B shows the first 24 hours after dosing on a linear concentration axis (days 20 and 26 data not shown). [Figure 2C] Mean plasma lurasidone concentrations in obese subjects (Figures 2C and 2D) are shown. Figure 2C shows the 72-hour study period on a logarithmic concentration axis (days 20 and 26 data not shown). [Figure 2D]Mean plasma lurasidone concentrations are shown in obese subjects (Figures 2C and 2D). Figure 2D shows the first 24 hours after dosing on a linear concentration axis (days 20 and 26 data not shown). [Figure 3]

[0018] The arithmetic mean (±standard error) ratios of lurasidone AUC during and after posaconazole administration divided by the AUC in the baseline control state in normal weight and obese subjects are shown. At all time points, the ratios were significantly different from 1.0. [Figure 4]

[0019] Figure 1 shows the relationship between plasma posaconazole concentrations (X-axis) and lurasidone AUC (Y-axis). The solid line represents the best-fit function determined by linear regression analysis. The fitted function is Y = 2.38 × 0.58 + 110.6. [Figure 5]

[0020] Figure 5 shows the mean (±SD) and log-transformed plasma posaconazole concentrations in normal weight and obese subjects during and after posaconazole administration. Figure 5A shows the linear concentration axis. Figure 5B shows the log concentration axis. [Figure 6A]

[0021] Mean (±SD) plasma ranolazine concentrations in normal weight subjects (Figure 6A) alone (Day 1), with posaconazole co-administration (Day 15), and after posaconazole discontinuation (Days 18-29) are shown. For kinetic analysis, see Table 10. Top: Linear concentration axis. Bottom: Logarithmic concentration axis. [Figure 6B] Mean (±SD) plasma ranolazine concentrations in obese subjects (Figure 6B) alone (day 1), with posaconazole co-administration (day 15), and after posaconazole discontinuation (days 18-29) are shown. For kinetic analysis, see Table 10. Top: Linear concentration axis. Bottom: Logarithmic concentration axis. [Figure 7]

[0022] Figure 7 shows the geometric mean ratios (GMR) and 90% CI for ranolazine AUC (Figure 7A) and Cmax (Figure 7B) compared to Day 1. The GMR=1.5 line refers to the levels observed during co-administration of ranolazine with diltiazem in pre-approval studies. AUC indicates the area under the concentration-time curve, and Cmax indicates the peak concentration. [Figure 8]

[0023] 1 shows the actual lurasidone AUC ratio measured in normal weight and obese subjects (dashed line) compared to the lurasidone AUC in patients that could be predicted from the posaconazole half-life (predicted lurasidone AUC ratio, solid line). [Figure 9]

[0024] The actual ranolazine AUC ratio measured in normal weight and obese subjects (dashed line) is shown compared to the ranolazine AUC in patients that could be predicted from the posaconazole half-life (predicted ranolazine AUC ratio, solid line). [Figure 10]

[0025] Shown is the predicted decay curve for encorafenib (solid line) and the maximum ("target safe level") GMR for AUC levels achieved by the methods disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0017]

[0026] All documents cited herein, including patents, applications, and non-patent publications, are hereby incorporated by reference in their entirety for all purposes.

[0018]

[0027] As used herein, "about" refers to a value that is greater than the indicated value. For example, "about" refers to a quantity that is ±5 to 10% of the demonstrative term it modifies, or Alternatively, the term "about" may indicate a range that can be estimated by a person skilled in the art from the context (e.g., about 50% of the midpoint). "About" also includes reference values. For example, if a BMI is about 40, it includes values ​​around 40.

[0019]

[0028] As used herein, a "patient" refers to a human subject. In some embodiments, the patient is male or female. In some embodiments, the patient may be an adult or a child.

[0020]

[0029] As used herein, "treatment" or "prescription" refers to the overall treatment regimen of a CYP3A4 substrate drug, if used concomitantly, during the 2-42 day period following discontinuation of posaconazole treatment. For example, the patient will be prescribed or administered (including self-administered) a reduced dose of the CYP3A4 substrate drug (e.g., about 50% or less of the baseline dose of the CYP3A4 substrate drug) during this period. In some embodiments, the patient will be advised to not take the CYP3A4 substrate drug, or the physician-prescribed dosing regimen, for 2-42 days, after which they can resume (or will be prescribed) the CYP3A4 substrate drug, e.g., at a baseline dose.

[0021]

[0030] As used herein, "treatment" and "treating" refer to (i) the act of preventing the occurrence of a particular disease or condition in a subject who may be predisposed to, but has not yet been diagnosed with, that disease or condition; (ii) the act of curing, treating, or suppressing the disease, i.e., preventing its development; or (iii) the act of ameliorating the disease by reducing or eliminating signs or symptoms and / or regression of the disease. In some embodiments, "treatment" and "treating" include the act of administering a therapeutically effective regimen, as defined herein.

[0022]

[0031] As used herein, a "therapeutically effective regimen" refers to a therapeutically effective regimen of sufficient duration or dosage to treat the disease or condition for which the drug is prescribed.

[0023]

[0032] As used herein, the term "patient" refers to a human subject who has symptoms that can be improved by posaconazole treatment and who is in need of treatment with a CYP3A4 substrate drug. For example, prior to receiving or being prescribed posaconazole, the patient simultaneously has a first symptom that can be improved by posaconazole treatment and a second symptom that can be improved by CYP3A4 substrate drug treatment. In some embodiments, the patient is first treated with posaconazole and then discontinues the posaconazole regimen and switches to a treatment described herein with a CYP3A4 substrate drug. In other embodiments, the patient develops symptoms that can be improved by CYP3A4 substrate drug treatment while being treated with posaconazole. In some embodiments, the patient discontinues the posaconazole regimen and switches to a treatment described herein with a CYP3A4 substrate drug. As used herein, the term "patient" does not include subjects who develop symptoms that can be improved by CYP3A4 substrate drug treatment at some time after discontinuing posaconazole treatment.

[0024]

[0033] As used herein, "posaconazole-treated patient" or "patient previously taking posaconazole" refers to a patient with symptoms that could be improved by posaconazole treatment.

[0025]

[0034] As used herein, "normal baseline C max " or "Baseline C max " is the mean C of a drug measured when administered at the same dose to a patient population that has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole), all other things being equal. max For example, if the CYP3A4 substrate drug is ranolazine, the "normal baseline C max " is used in a patient population that, other things being equal, has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole). The mean C of ranolazine measured at the dose of ranolazine max As another example, if the CYP3A4 substrate drug is lurasidone, the "normal baseline C maxis the mean C of lurasidone measured when the same dose of lurasidone is administered to patients who, other things being equal, have not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole). max As another example, when the CYP3A4 substrate drug is tadalafil, the "normal baseline C max is the mean C of tadalafil measured when the same dose of tadalafil is administered to patients who, other things being equal, have not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole). max is.

[0026]

[0035] As used herein, "normal baseline AUC" or "baseline AUC" refers to the mean AUC of a drug measured when the same dose is administered to a patient population that has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole) but other conditions are the same. For example, if the CYP3A4 substrate drug is ranolazine, the "normal baseline AUC" of ranolazine is the mean AUC of ranolazine measured when the same dose is administered to a patient population that has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole) but other conditions are the same. As another example, if the CYP3A4 substrate drug is lurasidone, the "normal baseline AUC" of lurasidone is the mean AUC of lurasidone measured when the same dose is administered to a patient population that has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole) but other conditions are the same. As yet another example, if the CYP3A4 substrate drug is tadalafil, the "typical baseline AUC" of tadalafil is the mean AUC of tadalafil measured when the same dose of tadalafil is administered to a patient population, all else being equal, that has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole).

[0027]

[0036] As used herein, "normal," "norm," and derivatives and variations thereof refer to a non-obese state in humans having at least one of the following characteristics: BMI less than about 35, %IBW less than about 150%, waist circumference less than about 42 inches, percent body fat less than about 40%, percent android body fat less than about 40%, percent dynoid body fat less than about 40%, and total body fat less than about 40 kg. Unless otherwise defined, "normal metabolizer" also refers to a normal metabolizer of CYP3A4.

[0028]

[0037] As used herein, the term "reference dose" refers to the dose of a particular CYP3A4 substrate drug that is listed in the FDA-approved manufacturer's labeling (e.g., the most recent FDA-approved labeling for a particular CYP3A4 drug, effective as of November 14, 2018) and that, all other things being equal, would be prescribed for a patient who has not previously been treated with a strong CYP3A4 inhibitor (e.g., posaconazole). It is common for a particular drug to be approved for multiple different indications, and each indication may have a different reference dose. Similarly, a drug is typically approved for different age groups, and each age group may have a different reference dose. In some embodiments, the reference dose is selected based on the patient's age and condition. Furthermore, some drug labels may recommend a range of doses to treat a particular indication, but for an individual patient, a specific dose within the recommended range is safe and therapeutically effective. In such embodiments, the safe and therapeutically effective dose for a particular patient is that patient's "reference dose." Specific reference doses for CYP3A4 substrate drugs are provided herein.

[0029]

[0038] Any reference herein to a CYP3A4 substrate drug also encompasses all pharmaceutically acceptable isomers (e.g., stereoisomers), solvates, hydrates, polymorphs, salts, and prodrugs (e.g., esters and phosphates). For example, a reference herein to solifenacin also includes its pharmaceutically acceptable salts, such as the succinate salt. As another example, A reference herein to naloxegol also includes its pharmaceutically acceptable salts, such as the oxalate salt. As another example, a reference herein to aripiprazole also includes its pharmaceutically acceptable prodrugs, such as aripiprazole lauroxil.

[0030]

[0039] As used herein, "stereoisomer" is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of enantiomers (racemates, racemic mixtures), geometric (cis / trans or E / Z) isomers, and isomers of compounds with multiple chiral centers that are not mirror images of one another (diastereoisomers). The CYP3A4 substrate drugs of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereoisomers, or enantiomers, or may exist as geometric isomers, and all isomers of such compounds are included in the present invention. Additionally, a CYP3A4 substrate drug can include any ratio for a mixture of stereoisomers, e.g., about 1:99 to about 99:1 (including all ratios and subranges therebetween), such as about 95:5, about 90:10, about 85:15, about 80:20, about 75:25, about 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, about 40:60, about 35:65, about 30:70, about 25:75, about 20:80, about 15:85, about 10:90, and about 95:5.

[0031]

[0040] The present disclosure also encompasses combinations of CYP3A4 substrate drugs described herein. Thus, according to any of the embodiments of the present disclosure, a patient can be treated with multiple CYP3A4 substrate drugs, such as lurasidone and ranolazine.

[0032]

[0041] The present disclosure provides methods for treating or prescribing treatment with a CYP3A4 substrate drug that is contraindicated for co-administration with a strong CYP3A4 inhibitor in a patient previously receiving posaconazole treatment, particularly when the patient has one or more of the physiological characteristics described herein and is subsequently treated with a CYP3A4 substrate drug. Thus, the present disclosure provides methods for treating different patient populations (e.g., "normal" patients, obese patients, and / or CYP3A4 intermediate or poor metabolizers (e.g., low metabolizers)) with a CYP3A4 substrate drug that is contraindicated for co-administration with a strong CYP3A4 inhibitor after discontinuing posaconazole treatment in the patient. The present disclosure also provides methods for initiating treatment with a CYP3A4 substrate drug for the treatment of various conditions or diseases in patients previously treated with posaconazole. The present disclosure also provides methods for preventing or reducing the risk of side effects associated with overexposure to a CYP3A4 substrate drug in normal patients, obese patients, and / or patients with CYP3A4 dysfunction (e.g., CYP3A4 poor metabolizers or CYP3A4 intermediate metabolizers) who are receiving a posaconazole regimen prior to treatment or prescription of the CYP3A4 substrate drug (including methods for treating the conditions described herein).

[0033]

[0042] In various embodiments, the present disclosure provides methods for administering or prescribing treatment with a CYP3A4 substrate drug to a patient previously treated with a therapeutically effective regimen that includes posaconazole, after a "drug holiday" period of about 2 to 42 days has elapsed since the posaconazole administration was discontinued. The drug holiday allows the plasma concentration of posaconazole to decrease to an appropriate level, allowing the CYP3A4 substrate drug to be administered thereafter without increasing the risk of serious side effects from the CYP3A4 substrate drug. As described herein, the applicants have discovered that a patient previously receiving posaconazole treatment can be safely administered a CYP3A4 substrate drug by administering or prescribing the first treatment with the CYP3A4 substrate drug (i.e., initiating treatment with the CYP3A4 substrate drug) after a "drug holiday" period of about 2 to 42 days has elapsed since the patient's posaconazole treatment was discontinued. However, since CYP3A4 substrate drugs are generally prohibited from being administered concomitantly with posaconazole, the necessity of such a drug-free period was not known until now. As described above, in some embodiments, the applicants have also discovered that, instead of a drug holiday, it is potentially safe to administer a CYP3A4 substrate drug to a patient previously receiving posaconazole treatment at a dose of about 50% or less of the reference dose of the CYP3A4 substrate drug for about 2 to 42 days after the patient's posaconazole treatment is discontinued. Similarly, such a dosing regimen was previously unknown.

[0034]

[0043] Cytochrome P450 3A4 (CYP3A4) is an enzyme that modifies small organic molecules, such as certain drugs (especially those described herein as "CYP3A4 substrate drugs"), thereby allowing the molecules to be metabolized and eliminated from the body. Some substances, so-called "CYP3A4 inhibitors," reduce the activity of the CYP3A4 enzyme, potentially increasing a patient's exposure to CYP3A4 substrate drugs. On the other hand, strong CYP3A4 inhibitors, when administered at appropriate doses, inactivate CYP3A4, potentially causing excessive increases in the plasma levels of co-administered CYP3A4 substrate drugs, potentially leading to dangerous situations. Therefore, co-administration of CYP3A4 substrate drugs and strong CYP3A4 inhibitors is prohibited.

[0035]

[0044] As used herein, the term "potent CYP3A4 inhibitor" refers to a drug that has been approved by the FDA as a potent CYP3A4 inhibitor and / or a drug that increases the AUC of a sensitive CYP3A4 substrate drug by at least about 5-fold or reduces the clearance of a sensitive CYP3A4 substrate drug by about 80% or more. The methods disclosed herein can be applied to the treatment of patients being treated with a potent CYP3A4 inhibitor, such as posaconazole, with a CYP3A4 substrate drug that is prohibited from being co-administered with any potent CYP3A4 inhibitor.

[0036]

[0045] Coadministration of posaconazole with CYP3A4 substrate drugs increases the QT interval c Clinically significant plasma levels of posaconazole with CYP3A4 substrate drugs can significantly increase levels of CYP3A4 substrate drugs, posing a risk of QT prolongation. Potential consequences of QT prolongation include arrhythmias, tachycardia, cardiac rhythm abnormalities, palpitations, dizziness, lightheadedness, sudden syncope, seizures, torsades de pointes, and cardiac death.

[0037]

[0046] For example, according to the drug label for posaconazole (NOXAFIL® label, revised September 2016), patients should not take cerolimus, pimozide, quinidine, HMG-CoA reductase inhibitors, ergot alkaloids, or QT inhibitors. c It is recommended to avoid coadministration of posaconazole with certain CYP3A4 substrate drugs, including those known to prolong the interval and cause cases of TdP. The NOXAFIL® label further warns that dose adjustments should be considered when posaconazole is coadministered with other drugs metabolized by CYP3A4, such as tacrolimus, cyclosporine, vinca alkaloids, and calcium channel blockers. However, the posaconazole label does not mention any need for a washout period or population stratification for patients between discontinuing posaconazole and initiating treatment with a CYP3A4 substrate.

[0038]

[0047] In some embodiments, the potent CYP3A4 inhibitor is posaconazole (i.e., Noxafil, Posanol). Currently, posaconazole is formulated as an oral suspension (40 mg / mL), an intravenous solution (18 mg / mL), and a delayed-release tablet (100 mg). According to the drug label (Merck), the current recommended dose for invasive Aspergillus and Candida infections is 300 mg twice daily for the first day and 300 mg once daily thereafter for the intravenous solution or delayed-release tablet, and 200 mg three times daily for the oral suspension. The current recommended dose for the treatment of oropharyngeal candidiasis is 100 mg twice daily for the first day and 100 mg once daily for 13 days for the oral suspension. Itraconazole and / or The currently recommended dose for the treatment of oropharyngeal candidiasis refractory to fluconazole is 400 mg twice daily for the first day as an oral suspension.

[0039]

[0048] In some embodiments, posaconazole can be used to treat fungal infections. In one embodiment, posaconazole can be used to treat Candida infections, such as oropharyngeal candidiasis. In one embodiment, posaconazole can be used to treat oropharyngeal candidiasis refractory to itraconazole and / or fluconazole. In one embodiment, posaconazole can be used to treat Aspergillus infections. In one embodiment, posaconazole can be used to treat Zygomycosis infections. In some embodiments, posaconazole can be used to prevent infections in patients who are at high risk for developing invasive Aspergillus and Candida infections due to severe immunodeficiency, such as patients with graft-versus-host disease (GVHD) who have undergone hematopoietic stem cell transplantation (HSCT) and patients with hematologic malignancies experiencing prolonged chemotherapy-induced neutropenia. In one embodiment, posaconazole can be used to treat Zygomycosis. In one embodiment, posaconazole can be indicated for the treatment of allergic bronchopulmonary aspergillosis. In one embodiment, posaconazole can be indicated for the prevention or treatment of recurrent esophageal candidiasis secondary to HIV infection. In one embodiment, posaconazole can be indicated for the treatment of Fusarium infections. In one embodiment, posaconazole can be indicated for the treatment of chronic or cavitary necrotizing pulmonary aspergillosis.

[0040]

[0049] As used herein, "CYP3A4 substrate drug" refers to a drug that is primarily metabolized by the CYP3A4 enzyme and is administered in a pharmaceutically acceptable dosage form (e.g., tablet, capsule, oral solution, injection, infusion, sustained-release or extended-release formulation thereof). In some embodiments, the CYP3A4 drug is lurasidone (Latuda). In some embodiments, the CYP3A4 drug is ranolazine (Ranexa). In some embodiments, the CYP3A4 substrate drug includes lumacaftor / ivacaftor (Orkambi). In some embodiments, In some embodiments, the CYP3A4 substrate drug includes venetoclax (Venclexta). In some embodiments, the CYP3A4 substrate drug includes trabectedin (Yondelis). In some embodiments, the CYP3A4 substrate drug includes ribociclib succinate (Kisqali). In some embodiments, the CYP3A4 substrate drug includes deflazacort (Emflaza). In some embodiments, the CYP3A4 substrate drug includes cinacalcet hydrochloride (Sensipar). In some embodiments, the CYP3A4 substrate drug includes pimavanserin tartrate (Nuplazid). In some embodiments, the CYP3A4 substrate drug includes aripiprazole lauroxyl (Aristada). In some embodiments, the CYP3A4 substrate drug includes cariprazine hydrochloride (Vraylar). In some embodiments, the CYP3A4 substrate drug includes simeprexa. In some embodiments, the CYP3A4 substrate drug includes everolimus (Afinitor, Afinitor Disperz, Zortress). In some embodiments, the CYP3A4 substrate drug includes saxagliptin hydrochloride (Onglyza). In this study, the CYP3A4 substrate drug was saxagliptin / metformin hydrochloride (Kombiglyze XR). In some embodiments, the CYP3A4 substrate drug includes ticagrelor (Brilinta). In some embodiments, the CYP3A4 substrate drug includes vilazodone hydrochloride (Viibryd). In some embodiments, the CYP3A4 substrate drug includes apixaban (Eliquis In some embodiments, the CYP3A4 substrate drug comprises tofacitinib citrate (Xeljanz). In some embodiments, the CYP3A4 substrate drug comprises eletriptan. In some embodiments, the CYP3A4 substrate drug comprises nilotinib hydrochloride hydrate (Tasigna). In some embodiments, the CYP3A4 substrate drug comprises nilotinib hydrochloride hydrate (Tasigna). In some embodiments, the CYP3A4 substrate drug includes dronedarone hydrochloride (Multaq). In some embodiments, the CYP3A4 substrate drug includes fluticasone propionate / salmeterol xinafoate (Advair Diskus). In some embodiments, the CYP3A4 substrate drug includes rivaroxaban (Xarel In some embodiments, the CYP3A4 substrate drug includes tadalafil (Cialis, Adcirca). In some embodiments, the CYP3A4 substrate drug includes colchicine (Colcrys). In some embodiments, the CYP3A4 substrate drug includes ibrutinib (Imbruvica). In some embodiments, the CYP3A4 substrate drug includes cobimetinib (Cotellis). In some embodiments, the CYP3A4 substrate drug is cabazitaxel (Jevtana In some embodiments, the CYP3A4 substrate drug includes tolvaptan (Samsca). In some embodiments, the CYP3A4 substrate drug includes fosaprepitant dimeglumine (Emend). In some embodiments, the CYP3A4 substrate drug includes aprepitant In some embodiments, the CYP3A4 substrate drug is succinic acid solyf. In some embodiments, the CYP3A4 substrate drug includes erlotinib hydrochloride (Tarceva). In some embodiments, the CYP3A4 substrate drug includes ad In some embodiments, the CYP3A4 substrate drug includes bosutinib monohydrate (Bosulif). In some embodiments, the CYP3A4 substrate drug includes sunitinib malate (Sutent). In some embodiments, the CYP3A4 substrate drug includes fesoterodine fumarate (Tobiaz). In some embodiments, the CYP3A4 substrate drug includes maraviroc (Selzentry). ... In some embodiments, the CYP3A4 substrate drug includes pazopanib hydrochloride (Votrient). In some embodiments, the CYP3A4 substrate drug includes aripiprazole (Abilify). In some embodiments, the CYP3A4 substrate drug includes axitinib (Inlyta). In some embodiments, the CYP3A4 substrate drug includes dapagliflozin / saxagliptin (Farxiga / Onglyza). In some embodiments, the CYP3A4 substrate drug comprises cabozantinib S-malate (Cabometyx). In some embodiments, the CYP3A4 substrate drug comprises cabozantinib S-malate (Cabometyx). In some embodiments, the product comprises ponatinib hydrochloride (Iclusig). In some embodiments, the CYP3A4 substrate drug includes isavuconazonium sulfate (Cresemba). In some embodiments, the CYP3A4 substrate drug includes lomitapide mesylate (Juxtapid). In some embodiments, the CYP3A4 substrate drug includes iloperidone (Fanapt). In some embodiments, the CYP3A4 substrate drug includes palbociclib (Ibrance). In some embodiments, the CYP 3A4 substrate drugs include levomilnacipran hydrochloride (Fetzima). In some embodiments, In some embodiments, the CYP3A4 substrate drug includes pimozide (Orap). In some embodiments, the CYP3A4 substrate drug includes pomalidomide (Pomalyst). In some embodiments, the CYP3A4 substrate drug includes abemaciclib (Verzenio). In some embodiments, the CYP3A4 substrate drug includes ivacaftor (Kalydeco). In some embodiments, the CYP3A4 substrate drug includes ruxolitinib phosphate (Jakafi). In some embodiments, the CYP3A4 substrate drug includes brexpiprazole (Rexulti). In some embodiments, the CYP3A4 substrate drug includes brexpiprazole (Rexulti). CYP3A4 substrate drugs include ivacaftor / tezacaftor (Symdeko). In some embodiments, the CYP3A4 substrate drug includes regorafenib (Stivarga). In some embodiments, the CYP3A4 substrate drug comprises daclatasvir (Daklinza). In some embodiments, the CYP3A4 substrate drug comprises crizotinib (Xalkori). In some embodiments, the CYP3A4 substrate drug includes naloxegol oxalate (Movantik). In some embodiments, the CYP3A4 substrate drug includes dabrafenib (Tafinlar). In some embodiments, the CYP3A4 substrate drug includes elbasvir and grazopeptide. In some embodiments, the CYP3A4 substrate drug includes olaparib (Lynparza). In some embodiments, the CYP3A4 substrate drug includes apalutamide (Erleada). In some embodiments, the CYP3A4 substrate drug includes brigatinib (Alunbrig). In some embodiments, the CYP3A4 substrate drug includes cannabidiol (Epidiolex). In some embodiments, the CYP3A4 substrate drug is copanlisib (Aliqopa). In some embodiments, the CYP3A4 substrate drug includes duvelisib (Copiktra). In some embodiments, the CYP3A4 substrate drug includes encorafenib (Braftovi). In some embodiments, the CYP3A4 substrate drug includes flibanserin (Addyi). In some embodiments, the CYP3A4 substrate drug includes ivabradine (Co In some embodiments, the CYP3A4 substrate drug includes ivosidenib (Tibsovo). In some embodiments, the CYP3A4 substrate drug includes panobinostat (Farydak). In some embodiments, the CYP3A4 substrate drug includes sonidegib (Odomzo). In some embodiments, the CYP3A4 substrate drug includes vemurafenib (Zelboraf). Other examples of CYP3A4 substrate drugs include HIV protease inhibitors (amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva, Telzir), indinavir (Crixivan), lopinavir (Kaletra), neruvinib (Zelboraf), and fluconazole (Zelboraf). finavir (Viracept), ritonavir (Norvir), saquinavir (Invirase, Forovase), tipranavir (Aptivus), etc.), benzodiazepines (alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), etc.), calcium channel blockers (amlodipine (Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine (HypoCa), benidipine (Coniel), cilnidipine (Atelec, Cinalong, Siscard), clevidipine (Cleviprex), isradipine (DynaCirc, Prescal), efonidipine (Landel), felodipine (Plendil), lacidipine (Motens, Lacipil), lercanidipine (Zanidip) ), manidipine (Calslot, Madipine), nicardipine (Cardene, Carden SR), nife Diazepam (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Ludipine (Baymycard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Baylotensin), pranidipine (Acalas, etc.), hydroxymethylglutaryl coenzyme A reductase tase inhibitors (atorvastatin (Lipitor, Ator), lovastatin (Mevacor, Altocor) , Altoprev), mevastatin (Compactin), simvastatin (Zocor, Lipex), etc.), Antitumor drugs (such as sorafenib (Nexavar) and sunitinib (Sutent)), non-sedating antihistamines Antihistamines (fexofenadine (Allegra), loratadine (Claritin), desloratadine (Clarinex), cetirizine (Zyrtec), levocetirizine (Xyza), etc.), immunosuppressants (serotonin, steroids, etc.), These include, but are not limited to, rosporin.

[0041]

[0050] In some embodiments, the CYP3A4 substrate drugs used in the methods disclosed herein are any drugs metabolized by CYP3A4, particularly drugs metabolized by CYP3A4 that are contraindicated in combination with strong CYP3A4 inhibitors or for which a dose adjustment is recommended when coadministered with a CYP3A4 inhibitor. In some embodiments, the methods described herein are applicable to treatment regimens in which one or more of the CYP3A4 substrate drugs described herein are used to treat patients who have previously been treated with posaconazole, e.g., treatment regimens involving the treatment of patients with a CYP3A4 substrate drug in combination with other drugs.

[0042]

[0051] In some embodiments, the CYP3A4 substrate drug is used to treat schizophrenia in adults and adolescents (ages 13-17), depressive episodes associated with bipolar disorder type 1 (bipolar depression) in adults and children (ages 10-17) (either as monotherapy or adjunctive therapy with lithium or valproate), moderate bipolar depression, severe bipolar depression, and severe bipolar depression with acute suicidal ideation and behavior (ASIB), chronic angina, cystic fibrosis in patients 6 years of age and older who are homozygous for the F508del mutation in the CFTR gene, chronic lymphocytic leukemia in patients with a chromosome 17 deletion who have received at least one prior therapy, and unresectable or metastatic liposarcoma or smooth muscle tumors in patients who have received a prior anthracycline-containing regimen. Breast cancer, hormone receptor (HR)-positive advanced or metastatic breast cancer in postmenopausal women, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, negative advanced or metastatic breast cancer (in combination with aromatase inhibitors in postmenopausal women), Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients on dialysis with chronic kidney disease (CKD), hypercalcemia in patients with primary HPT or parathyroid carcinoma who are unable to undergo parathyroidectomy despite being recommended for parathyroidectomy based on serum calcium levels, hallucinations and delusions due to Parkinson's disease psychosis, schizophrenia, acute manic or mixed episodes associated with bipolar disorder type 1, chronic hepatitis C (CHC) infection (compensated hepatitis) as a component of a combination antiviral treatment regimen with pegylated interferon alfa and ribavirin for HCV genotype 1-infected subjects with the disease; in postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+BC) in combination with exemestane after treatment failure with letrozole or anastrozole; advanced neuroendocrine tumors of pancreatic origin (PNET); unresectable, locally advanced, or metastatic well-differentiated nonfunctioning neuroendocrine tumors (NET) of gastrointestinal (GI) or pulmonary origin; advanced renal cell carcinoma (RCC) (e.g., after treatment with sunitinib or sorafenib); after failed treatment with cerebrospinal fluid (CSF), renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, TSC in patients with subependymal giant cell astrocytoma (SEGA) requiring treatment intervention but not candidates for surgical resection, type 2 diabetes in adults (as an adjunct to diet and exercise to improve glycemic control), major depressive disorder (MDD), thrombotic cardiovascular events (e.g., cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome (ACS), stroke and systemic embolism in patients with non-valvular atrial fibrillation, and pulmonary embolism (PE) in patients undergoing hip or knee replacement surgery. Deep vein thrombosis (DVT), which may induce DVT, DVT, PE, recurrent DVT and PE associated with initial treatment, moderate to severe active rheumatoid arthritis in patients with an inadequate response or resistance to methotrexate, acute migraine with or without aura, Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in chronic and accelerated phases in newly diagnosed patients or those with resistance or intolerance to prior treatment including imatinib, and patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or are being cardioverted. atrial fibrillation (AF), asthma in patients aged 4 years or older, obstructive pulmonary disease and reduction of exacerbations in patients with chronic obstructive pulmonary disease, erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHO classification group 1) (for the purpose of improving exercise capacity), gout flares, familial Mediterranean fever, antiretroviral therapy, anxiety disorder, panic disorder, seizures, insomnia, hypertension, cardiovascular disease, hyperlipidemia, primary renal cancer, advanced primary liver cancer, radioactive iodine-resistant advanced thyroid cancer, cancers such as renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor, mantle cell lymphoma in patients who have received at least one prior treatment,Chronic lymphocytic leukemia / small lymphocytic lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma with deletion of the short arm of chromosome 17, Waldenstrom macroglobulinemia, marginal zone lymphoma in patients who required systemic treatment and who have received at least one anti-CD20 treatment, BRAF, Unresectable or metastatic melanoma with V600E or V600K mutations, allergy, transplantation, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, treatment of clinically significant polycythemia and euvolemic hyponatremia, including patients with heart failure and syndrome of abnormal antidiuretic hormone (SIADH), initial and repeat high-dose cisplatin-containing highly emetogenic cancer chemotherapy (HEC). Prevention of acute and delayed nausea and vomiting associated with the initial and repeated courses of moderately emetogenic cancer chemotherapy (MEC); overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency; metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test and have received first-line treatment, maintenance treatment, or second-line or higher treatment after progression; locally advanced, unresectable, or metastatic pancreatic cancer in combination with imatinib; HER-2 positive metastatic breast cancer previously treated with trastuzumab and a taxane, either separately or in combination, in patients who have previously been treated for metastatic disease or who have developed disease recurrence during or within 6 months of completing adjuvant therapy; adult Ph+ chronic myeloid leukemia (CML) in chronic, accelerated, or acute phase with resistance or intolerance to previous therapy; gastrointestinal disease after disease progression or intolerance to imatinib mesylate stromal tumors (GIST), advanced renal cell carcinoma (RCC), advanced well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable, locally advanced, or metastatic disease, CCR5-tropic HIV-1 infection in patients aged 2 years or older weighing at least 10 kg in combination with other antiretrovirals, advanced renal cell carcinoma, advanced soft tissue sarcoma that has previously received chemotherapy, manic and mixed episodes associated with bipolar disorder type 1, major depressive disorder, hyperirritability associated with autistic disorder, Tourette's syndrome, and idiopathic rheumatoid arthritis. agitation associated with schizophrenia or bipolar mania; advanced renal cell carcinoma after failure of one prior systemic therapy; improving glycemic control in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with dapagliflozin or already treated with dapagliflozin and saxagliptin; advanced metastatic medullary thyroid carcinoma (MTC); advanced renal cell carcinoma (RCC) that has received prior antiangiogenic therapy; chronic, accelerated, or acute phase chronic myeloid leukemia (CML) or Ph+ ALL in adults for whom other tyrosine kinase inhibitor (TKI) therapy is not indicated; To reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apoB), and non-high-density lipoprotein cholesterol (non-HDL-C) in adults with T315I-positive CML (chronic, accelerated, or acute phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), invasive aspergillosis, invasive mucormycosis, and homozygous familial hypercholesterolemia (HoFH), as well as in adults with schizophrenia and as initial endocrine therapy in postmenopausal women. in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with matase inhibitors or disease progression after endocrine therapy; major depressive disorder (MDD); suppression of motor and vocal tics in patients with Tourette's syndrome who have not adequately responded to standard treatment; and treatment of multiple myeloma in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and who have shown disease progression within 60 days of completing the last treatment; allergies; transplants; or previous docetaxel hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, treatment of clinically significant polycythemia and euvolemic hyponatremia, including patients with heart failure and syndrome of abnormal antidiuretic hormone (SIADH); prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy (HEC) including high doses of cisplatin; prevention of delayed nausea and vomiting associated with initial and repeated courses of moderately emetogenic cancer chemotherapy (MEC); urge urinary incontinence; urgency;and overactive bladder with symptoms of frequent urination, metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test and who have received first-line treatment after progression, maintenance treatment, or second-line or higher treatment, locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine, previously treated with trastuzumab and a taxane in patients who have previously been treated for metastatic disease or who have developed disease recurrence during or within 6 months of completing adjuvant therapy. separately or in combination with HER-2 positive metastatic breast cancer, adult Ph+ chronic myeloid leukemia (CML) in chronic, accelerated, or acute phase with resistance or intolerance to previous therapy, gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC), advanced well-differentiated pancreatic neuroendocrine tumor (pNET) in patients with unresectable, locally advanced, or metastatic disease, CCR5-tropic HIV-1 infection in patients 2 years of age or older weighing at least 10 kg, advanced renal cell carcinoma, Advanced soft tissue sarcoma who have received previous chemotherapy, manic and mixed episodes associated with bipolar disorder type 1, major depressive disorder, irritability associated with autistic disorder, Tourette's disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one prior systemic therapy, improving glycemic control in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with dapagliflozin or already treated with dapagliflozin and saxagliptin, advanced metastatic medullary thyroid carcinoma (MTC), and adults who have previously received antiangiogenic therapy. Low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in patients with previously treated advanced renal cell carcinoma (RCC), adult chronic, accelerated, or acute phase chronic myeloid leukemia (CML) or Ph+ALL for whom other tyrosine kinase inhibitor (TKI) therapy is not indicated, adult T315I-positive CML (chronic, accelerated, or acute phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), invasive aspergillosis, invasive mucormycosis, and homozygous familial hypercholesterolemia (HoFH),Apolipoprotein B (apoB), and non-high density, To reduce lipoprotein cholesterol (non-HDL-C), in adults with schizophrenia, in combination with aromatase inhibitors as initial endocrine therapy in postmenopausal women or fulvestrant in women with disease progression after endocrine therapy, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, major depressive disorder (MDD), and suppression of motor and vocal tics in patients with Tourette's syndrome who have not responded adequately to standard treatment, and at least two previous therapies, including lenalidomide and a proteasome inhibitor. Treatment of multiple myeloma in patients who have received chemotherapy and have shown disease progression within 60 days of completing their last treatment; non-small cell lung cancer (NSCLC) with no disease progression after four cycles of platinum-based first-line chemotherapy; locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen; locally advanced, unresectable, or metastatic pancreatic cancer; overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency; advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib; tuberous sclerosis ( As monotherapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy, in combination with fulvestrant, and with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TS), renal angiomyolipoma, tuberous sclerosis complex, and women with CFTR-related HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy and prior chemotherapy in the metastatic setting, who are responsive to ivacaftor based on clinical and / or in vitro assay data. Cystic fibrosis (CF) in patients 2 years of age or older with one mutation in a child; germline BRCA-mutated advanced ovarian cancer in adult patients who have been treated with three or more prior lines of chemotherapy and are suspected of being adverse; intermediate-risk or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis; patients with polycythemia vera who have had an inadequate response to or are intolerant to hydroxyurea; as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD); schizophrenia;Cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that responds to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence; metastatic colorectal cancer (CRC) patients, previously treated with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy; locally advanced, unresectable or opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with metastatic gastrointestinal stromal tumors (GISTs), hepatocellular carcinoma (HCC) previously treated with sorafenib, chronic HCV genotype 1 or 3 infection with sofosbuvir with or without ribavirin, patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1 positive as detected by an FDA-approved test, and patients with chronic pain related to a previous cancer or its treatment and who do not require frequent (e.g., weekly) opioid dose escalation, and BRAF as detected by an FDA-approved test. unresectable or metastatic melanoma in patients with a V600E mutation, in combination with trametinib, unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation as detected by an FDA-approved test, adjuvant treatment of patients with melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test and lymph node metastasis after complete resection, metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation as detected by an FDA-approved test, locally advanced or metastatic anaplastic thyroid carcinoma (ATC) in patients with a BRAF V600E mutation for which there are no satisfactory local treatment options, treatment of chronic HCV genotype 1 or 4 infection in adults with or without ribavirin, treatment of patients with non-metastatic castration-resistant prostate cancer, anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; Treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; Treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; BRAF as detected by an FDA-approved test Treatment of patients with unresectable or metastatic melanoma harboring a V600E or V600K mutation in combination with binimetinib; treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), characterized by low sexual desire, that causes significant distress or interpersonal difficulties and is not due to a coexisting medical or psychiatric condition; relationship problems; or the influence of drugs or other medicinal substances; stable disease with a left ventricular ejection fraction of 35% or less, with a resting heart rate of 70 beats per minute or more, and taking a maximum tolerated dose of a beta-blocker or for whom beta-blocker use is contraindicated. reducing the risk of hospitalization due to worsening heart failure in patients with symptomatic chronic heart failure; treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; treatment of patients with multiple myeloma who have received at least two prior regimens containing bortezomib and an immunomodulatory agent; treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy or who are not candidates for surgery or radiation therapy; treatment of patients with unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; and treatment of patients with Erdheim-Chester disease with a BRAF V600 mutation.

[0043]

[0052] In some embodiments, CYP3A4 substrate drugs are indicated for the treatment of schizophrenia in adults and adolescents (13-17 years of age) and depressive episodes associated with bipolar disorder type I (bipolar depression), moderate bipolar depression, severe bipolar depression, and severe bipolar depression with acute suicidal ideation and behavior (ASIB) in adults and children (10-17 years of age), either as monotherapy or adjunctive therapy with lithium or valproate.

[0044]

[0053] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of chronic angina pectoris.

[0045]

[0054] In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of cystic fibrosis in patients aged 6 years and older who are homozygous for the F508del mutation in the CFTR gene, for example.

[0046]

[0055] In one embodiment, CYP3A4 substrate drugs are indicated for the treatment of chronic lymphocytic leukemia in patients with a deletion of the short arm of chromosome 17 who have received at least one prior therapy.

[0047]

[0056] In one embodiment, CYP3A4 substrate drugs may be indicated, for example, for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have previously received an anthracycline-containing regimen.

[0048]

[0057] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of advanced or metastatic breast cancer, for example, in hormone receptor (HR)-positive postmenopausal women, or human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. In a further embodiment, the CYP3A4 substrate drug may be indicated for the treatment of HER2-negative advanced or metastatic breast cancer in postmenopausal women, for example, in combination with an aromatase inhibitor as initial endocrine therapy.

[0049]

[0058] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of Duchenne muscular dystrophy (DMD).

[0050]

[0059] In one embodiment, a CYP3A4 substrate drug can be indicated for the treatment of secondary hyperparathyroidism (HPT), for example, in patients on dialysis suffering from chronic kidney disease (CKD). In one embodiment, a CYP3A4 substrate drug can be indicated for the treatment of hypercalcemia, for example, in patients with parathyroid carcinoma. In one embodiment, a CYP3A4 substrate drug can be indicated for the treatment of hypercalcemia, for example, in patients with primary hyperparathyroidism who are recommended for parathyroidectomy based on serum calcium levels but are unable to undergo parathyroidectomy.

[0051]

[0060] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of hallucinations and delusions due to Parkinson's disease psychosis.

[0052]

[0061] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of schizophrenia.

[0053]

[0062] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of acute manic or mixed episodes associated with type I bipolar disorder.

[0054]

[0063] In one embodiment, CYP3A4 substrate drugs are indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen with pegylated interferon alpha and ribavirin for HCV genotype 1-infected subjects with compensated liver disease.

[0055]

[0064] In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+BC), e.g., in combination with exemestane after treatment failure with letrozole or anastrozole. In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with advanced neuroendocrine tumors of pancreatic origin (PNET). In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with advanced, well-differentiated, nonfunctioning neuroendocrine tumors (NET) of unresectable, locally advanced, or metastatic gastrointestinal (GI) or pulmonary origin. In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with advanced renal cell carcinoma (RCC), e.g., after treatment failure with sunitinib or sorafenib. In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) who do not require immediate surgery. In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of TSC in patients with subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not candidates for surgical resection.

[0056]

[0065] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of type II diabetes in adults, for example, as an adjunct to diet and exercise to improve glycemic control.

[0057]

[0066] In one embodiment, CYP3A4 substrate drugs may be indicated for reducing the incidence of thrombotic cardiovascular events (eg, cardiovascular death, myocardial infarction, stroke) in patients with acute coronary syndrome (ACS).

[0058]

[0067] In one embodiment, the CYP3A4 substrate drug is used to treat major depressive disorder (MDD). It can be adapted to the location.

[0059]

[0068] In one embodiment, a CYP3A4 substrate drug can be indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In one embodiment, a CYP3A4 substrate drug can be indicated for preventing deep vein thrombosis (DVT), which can lead to pulmonary embolism (PE), for example, in patients who have undergone hip or knee replacement surgery. In one embodiment, a CYP3A4 substrate drug can be indicated for treating DVT or PE. In one embodiment, a CYP3A4 substrate drug can be indicated for reducing the risk of recurrent DVT and PE associated with initial treatment.

[0060]

[0069] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of moderate to severe active rheumatoid arthritis, for example, in patients who have shown an inadequate response or resistance to methotrexate.

[0061]

[0070] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of acute migraine headaches with or without aura.

[0062]

[0071] In one embodiment, CYP3A4 substrate drugs are indicated for the treatment of chronic and accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML), for example in newly diagnosed patients or patients who are resistant or intolerant to prior treatment including imatinib.

[0063]

[0072] In one embodiment, CYP3A4 substrate drugs may be indicated for reducing the risk of hospitalization for atrial fibrillation (AF), for example, in patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or are being cardioverted.

[0064]

[0073] In one embodiment, a CYP3A4 substrate drug can be indicated for the maintenance treatment of asthma, for example, in patients aged 4 years or older. In one embodiment, a CYP3A4 substrate drug can be indicated for the maintenance treatment of obstructive pulmonary disease and exacerbation reduction in patients with chronic obstructive pulmonary disease.

[0065]

[0074] In one embodiment, the CYP3A4 substrate drug can be used to treat erectile dysfunction (ED). In one embodiment, the CYP3A4 substrate drug can be used to treat benign prostatic hyperplasia (BPH). In one embodiment, the CYP3A4 substrate drug can be used to treat pulmonary arterial hypertension (PAH) (WHO Class 1) for the purpose of improving exercise capacity.

[0066]

[0075] In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of gout flares. In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of familial Mediterranean fever.

[0067]

[0076] In one embodiment, CYP3A4 substrate drugs can be used to treat mantle cell lymphoma in patients who have received at least one prior therapy. In one embodiment, CYP3A4 substrate drugs can be used to treat chronic lymphocytic leukemia / small lymphocytic lymphoma. In one embodiment, CYP3A4 substrate drugs can be used to treat chronic lymphocytic leukemia / small lymphocytic lymphoma with chromosome 17 deletion.

[0068]

[0077] In one embodiment, a CYP3A4 substrate drug can be indicated for Waldenstrom's macroglobulinemia.

[0069]

[0078] In one embodiment, CYP3A4 substrate drugs may be indicated for marginal zone lymphoma in patients who require systemic treatment and who have received at least one prior anti-CD20-based treatment.

[0070]

[0079] In one embodiment, CYP3A4 substrate drugs may be indicated for chronic or metastatic melanoma with BRAF V600E or V600K mutations.

[0071]

[0080] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

[0072]

[0081] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of clinically significant polycythemia and euvolemic hyponatremia, including in patients with heart failure and syndrome of abnormal antidiuretic hormone (SIADH).

[0073]

[0082] In one embodiment, CYP3A4 substrate drugs may be indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy (HEC), including high doses of cisplatin.

[0074]

[0083] In one embodiment, CYP3A4 substrate drugs may be indicated for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

[0075]

[0084] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of overactive bladder accompanied by symptoms of urge incontinence, urgency, and urinary frequency.

[0076]

[0085] In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test and who are receiving first-line treatment after progression, maintenance treatment, or second-line or higher treatment.

[0077]

[0086] In one embodiment, CYP3A4 substrate drugs are indicated in combination with gemcitabine for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

[0078]

[0087] In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of patients with HER-2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, either separately or in combination, during or within 6 months of completing adjuvant therapy, and in patients who have previously been treated for metastatic disease or who have developed disease recurrence.

[0079]

[0088] In one embodiment, a CYP3A4 substrate drug may be indicated for the treatment of adult patients with chronic, accelerated, or acute phase Ph+ chronic myeloid leukemia (CML) who have resistance or intolerance to previous therapy.

[0080]

[0089] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of gastrointestinal stromal tumors (GIST) following disease progression or intolerance to imatinib mesylate.

[0081]

[0090] In one embodiment, the CYP3A4 substrate drug is used in the treatment of patients with unresectable, locally advanced, or metastatic disease, including advanced renal cell carcinoma (RCC); advanced well-differentiated pancreatic neuroendocrine tumor (PNT); It can be applied to the treatment of pNETs.

[0082]

[0091] In one embodiment, a CYP3A4 substrate drug is indicated for the treatment of CCR5-tropic HIV-1 infection only in patients aged 2 years or older weighing at least 10 kg in combination with other antiretroviral drugs.

[0083]

[0092] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of patients with advanced renal cell carcinoma.

[0084]

[0093] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of patients with advanced soft tissue sarcoma who have previously received chemotherapy.

[0085]

[0094] In one embodiment, CYP3A4 substrate drugs are indicated for the treatment of acute manic and mixed episodes associated with type 1 bipolar disorder.

[0086]

[0095] In one embodiment, the CYP3A4 substrate drug may be indicated for the adjunctive treatment of major depressive disorder.

[0087]

[0096] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of hypersensitivity associated with autistic disorder.

[0088]

[0097] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of Tourette's syndrome.

[0089]

[0098] In one embodiment, the CYP3A4 substrate drug may be indicated for the treatment of agitation associated with schizophrenia or bipolar mania.

[0090]

[0099] In one embodiment, CYP3A4 substrate drugs may be indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

[0091]

[0100] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug inhibited by dapagliflozin. It can be indicated for improving glycemic control in adults with type 2 diabetes mellitus (T2DM) who are poorly controlled or who are already being treated with dapagliflozin and saxagliptin.

[0092]

[0101] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for the treatment of progressive metastatic medullary thyroid cancer. It can be applied to the treatment of patients with cancer (MTC).

[0093]

[0102] In one embodiment, the CYP3A4 substrate drug is administered to a patient who has previously received anti-angiogenic therapy. It can be indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have previously undergone chemotherapy.

[0094]

[0103] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that inhibits other tyrosine kinases. The drug can be indicated for the treatment of adult patients with chronic, accelerated, or acute phase chronic myeloid leukemia (CML) or Ph+ ALL for whom thyroid cancer (TKI) therapy is not indicated.

[0095]

[0104] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for T315I-positive CML (chronic It can be indicated for the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), whether in relapsed, accelerated, or acute phase.

[0096]

[0105] In one embodiment, the CYP3A4 substrate drug is used to treat invasive aspergillosis. It can be adapted to the location.

[0097]

[0106] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for patients with homozygous familial hypercholesterolemia. It can be indicated for the treatment of invasive mucormycosis, for reducing low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apoB), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with terolemia (HoFH).

[0098]

[0107] In one embodiment, the CYP3A4 substrate drug is suitable for the treatment of schizophrenia in adults. We can respond to your requests.

[0099]

[0108] In one embodiment, the CYP3A4 substrate drug is administered to a patient in the early stages of menopause in postmenopausal women. It is indicated for the treatment of hormone receptor (HR)-positive; human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as endocrine therapy, or in combination with fulvestrant in women with disease progression after endocrine therapy.

[0100]

[0109] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 inhibitor for the treatment of major depressive disorder (MDD). Treatment can be adapted.

[0101]

[0110] In one embodiment, the CYP3A4 substrate drug is administered to patients who do not respond adequately to standard treatment. It can be used to suppress motor and vocal tics in patients with Tourette's syndrome.

[0102]

[0111] In one embodiment, the CYP3A4 substrate drug is lenalidomide and protein. It may be indicated for the treatment of multiple myeloma in patients who have received at least two prior therapies, including asome inhibitors, and who have shown disease progression within 60 days of completing the last therapy.

[0103]

[0112] In one embodiment, the CYP3A4 substrate drug is a platinum-based first-line It may be indicated for the treatment of non-small cell lung cancer (NSCLC) in patients with no disease progression after four cycles of chemotherapy.

[0104]

[0113] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug having at least one previous It can be indicated for the treatment of locally advanced or metastatic NSCLC after failure of chemotherapy regimens.

[0105]

[0114] In one embodiment, the CYP3A4 substrate drug is It can be applied to the treatment of metastatic pancreatic cancer.

[0106]

[0115] In one embodiment, the CYP3A4 substrate drug is used to treat urge urinary incontinence, urgency, and It can be used to treat overactive bladder accompanied by symptoms of urinary frequency and urinary frequency.

[0107]

[0116] In one embodiment, the CYP3A4 substrate is sunitinib or sorafenib. It may be indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with rituximab.

[0108]

[0117] In one embodiment, the CYP3A4 substrate drug is used to treat a condition that requires intervention but is curable. It can be indicated for the treatment of subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC) that are not amenable to curative surgical resection.

[0109]

[0118] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate for renal angiomyolipoma and nodular It can be applied to the treatment of sclerosis.

[0110]

[0119] In one embodiment, the CYP3A4 substrate drug is Fulvestral in women. The drug can be indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression after endocrine therapy in combination with chemotherapy.

[0111]

[0120] In one embodiment, the CYP3A4 substrate drug is used in combination with endocrine therapy and metastatic disease. It can be used in combination with fulvestrant as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after prior chemotherapy in this setting.

[0112]

[0121] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that is Based on the assay data, it can be indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have a single mutation in the CFTR gene that responds to ivacaftor.

[0113]

[0122] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug administered after three or more prior chemotherapy regimens. The present invention may be indicated for the treatment of germline BRCA-mutated advanced ovarian cancer in adult patients who have been treated with prior lines of chemotherapy, or who are suspected of being at risk of adverse outcomes.

[0114]

[0123] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for primary myelofibrosis, erythroblastosis, It may be indicated for the treatment of intermediate-risk or high-risk myelofibrosis, including post-polycythemia myelofibrosis and post-essential thrombocythemia myelofibrosis.

[0115]

[0124] In one embodiment, the CYP3A4 substrate drug is a drug that is insensitive to hydroxyurea. It may be indicated for the treatment of patients with polycythemia vera who have responded adequately or who are intolerant to hydroxyurea.

[0116]

[0125] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 inhibitor for the treatment of major depressive disorder (MDD). It can be indicated as an adjunct therapy to antidepressants for treatment.

[0117]

[0126] In one embodiment, the CYP3A4 substrate drug is indicated for the treatment of schizophrenia. It is possible.

[0118]

[0127] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for the F508del mutation. Tezacaftor / ivacaftor is indicated for the treatment of patients aged 12 years and older with cystic fibrosis (CF) who are homozygous for or have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and who respond to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence.

[0119]

[0128] In one embodiment, the CYP3A4 substrate drug is a fluoropyrimidine It can be indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been treated with oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy.

[0120]

[0129] In one embodiment, the CYP3A4 substrate drug is a drug previously administered with imatinib mesylate. and can be indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumors (GIST) who have been treated with sunitinib malate.

[0121]

[0130] In one embodiment, the CYP3A4 substrate drug is a drug previously treated with sorafenib. In selected patients, it can be indicated for the treatment of hepatocellular carcinoma (HCC).

[0122]

[0131] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for chronic HCV genotype 1 or It can be indicated for use with sofosbuvir, with or without ribavirin, for the treatment of 3 infections.

[0123]

[0132] In one embodiment, the CYP3A4 substrate drug is an FDA approved The present invention may be indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who are anaplastic lymphoma kinase (ALK) or ROS1 positive as detected by the above tests.

[0124]

[0133] In one embodiment, the CYP3A4 substrate drug is a drug related to a previous cancer or its treatment. It can be indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain who do not require frequent (e.g., weekly) opioid dose escalation.

[0125]

[0134] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that is approved by an FDA. The present invention may be indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation as detected by immunohistochemistry.

[0126]

[0135] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that is approved by an FDA. It may be indicated in combination with trametinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by immunohistochemistry.

[0127]

[0136] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that is approved by an FDA. It may be indicated in combination with trametinib for the treatment of patients with melanoma with BRAF V600E or V600K mutations as detected by ELISA and lymph node metastases after complete resection.

[0128]

[0137] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug that is approved by an FDA. It can be indicated in combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by ELISA.

[0129]

[0138] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 inhibitor for which satisfactory local treatment options are not available. It may be indicated in combination with trametinib for the treatment of locally advanced or metastatic anaplastic thyroid carcinoma (ATC) with a BRAF V600E mutation that is not present.

[0130]

[0139] In one embodiment, the CYP3A4 substrate drug is a CYP3A4 substrate drug for adults with chronic HCV genotype It can be indicated for the treatment of 1 or 4 infections, with or without ribavirin.

[0131]

[0140] Other examples of conditions or diseases for which CYP3A4 substrate drugs are prescribed include antiretroviral drugs. These conditions include, but are not limited to, HIV / AIDS, anxiety disorders, panic disorders, seizures, insomnia, hypertension, cardiovascular disease (e.g., myocardial infarction, stroke, and angina), hyperlipidemia, cancers such as primary kidney cancer, advanced primary liver cancer, radioactive iodine-resistant advanced thyroid cancer, renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumors, allergies, transplantation, and the like.

[0132]

[0141] As mentioned above, strong CYP3A4 inhibitors (including posaconazole) Posaconazole accumulates in the patient's body and reduces or interferes with the metabolism of CYP3A4 substrate drugs, even after treatment with other drugs (including but not limited to posaconazole) is discontinued. Therefore, patients who previously took posaconazole and are subsequently treated with a CYP3A4 substrate may have plasma levels of the CYP3A4 substrate that are higher than those of otherwise identical patients not treated with posaconazole. The present specification, in various embodiments, describes a treatment regimen of a CYP3A4 substrate drug administered to a patient who has previously received multiple doses of a strong CYP3A4 inhibitor (e.g., posaconazole) for approximately 2 to 21 days after discontinuing treatment with the strong CYP3A4 inhibitor. In some embodiments, the treatment regimen includes a treatment or prescription in which the CYP3A4 substrate drug is administered at a dose of 50% or less of the reference dose for approximately 2 to 21 days after discontinuing posaconazole treatment. As used herein, a dose of less than 50% of the reference dose of the CYP3A4 inhibitor can be anywhere from 0% (i.e., no administration) to about 50% of the reference dose of the CYP3A4 inhibitor for 2 to 21 days. Thus, in some embodiments, the treatment regimens disclosed herein include postponing the first administration of a CYP3A4 substrate drug for about 2 to 21 days after discontinuing posaconazole treatment, or administering treatment with a reduced dose of the CYP3A4 substrate drug for about 2 to 21 days after discontinuing posaconazole treatment. The methods described herein can be applied to patients who have been taking posaconazole but have symptoms that can be improved with treatment with a CYP3A4 substrate drug, including normal patients (non-obese normal metabolizers), obese patients, poor metabolizers, intermediate metabolizers, or combinations thereof.

[0133]

[0142] In some embodiments, discontinuation of posaconazole (i.e., posaconazole about 2 to about 42 days, e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, from the start of treatment with a CYP3A4 substrate drug (i.e., the first administration in a CYP3A4 regimen with any of the CYP3A4 substrate drugs described herein) , about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days (including all ranges and subranges). In some embodiments, the patient is a "normal" patient (i.e., a patient with "normal" CYP3A4 enzyme function (often referred to in the art as a "normal metabolizer") and normal weight, e.g., a BMI in the range of 18.5 to 24.9). In other embodiments, the patient is a patient with one of the physiological characteristics described herein. For example, patients who are considered obese and / or have levels of CYP3A4 enzyme activity that are referred to in the art as low or intermediate activity.

[0134]

[0143] The period between the discontinuation or cessation of posaconazole treatment and the end of treatment with a CYP3A4 substrate drug The "delay" or waiting period before initiation can be considered the time that elapses between the discontinuation of posaconazole treatment and the first dose of treatment with a CYP3A4 substrate drug. One of ordinary skill in the art will understand that an additional dose of a CYP3A4 substrate drug is typically administered or prescribed thereafter. However, the "delay" or "drug holiday" period described herein refers only to the time between the discontinuation of posaconazole treatment and the first dose of treatment with a CYP3A4 substrate drug.

[0135]

[0144] In an alternative embodiment, instead of postponing treatment with a CYP3A4 substrate drug, After discontinuing posaconazole treatment, patients should receive 50% or less of the CYP3A4 substrate drug at a dose of 50% or less of the reference dose (the amount listed as the patient's recommended dose in the FDA-approved labeling for the CYP3A4 substrate drug), e.g., 50% or less, 49% or less, 48% or less, 47% or less, 46% or less, 45% or less, 44% or less, 43% or less, 42% or less, 41% or less, 40% or less, 39% or less, 38% or less, or 37% or less of the reference dose. , 36% or less, 35% or less, 34% or less, 33% or less, 32% or less, 31% or less, 30% or less, 29% or less, 28% or less, 27% or less, 26% or less, 25% or less, 24% or less, 23% or less, 22% or less, 21% or less, 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, or 10% or less (including all ranges and subranges thereof) ) for at least about 2 to 42 days, e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days (including all ranges and subranges thereof) after discontinuing the posaconazole regimen.

[0136]

[0145] In a further alternative embodiment, in response to a CYP3A4 substrate drug, the patient , a CYP3A4 substrate drug at a dose of less than 100% of the reference dose (the amount listed as the patient's recommended dose in the FDA-approved labeling for the CYP3A4 substrate drug), e.g., about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of the reference dose (including all ranges and subranges thereof), for at least about 2 to 42 days, e.g., about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days after discontinuing the posaconazole regimen. The administration may be administered or prescribed for about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, or about 42 days (including all ranges and subranges thereof).

[0137]

[0146] For "normal" patients (e.g., non-obese CYP3A4 normal metabolizers) In addition to methods of administering or prescribing treatment with a CYP3A4 substrate drug, the present disclosure also discloses methods of administering or prescribing treatment with a CYP3A4 substrate drug to a patient who has at least one physiological characteristic described herein and who is receiving multiple doses of posaconazole. Treatment with the CYP3A4 substrate drug is initiated or prescribed to be initiated after a delay time described herein (or the first dose begins after posaconazole treatment is discontinued). Alternatively, as described herein, treatment is administered or prescribed at a reduced dose (any amount less than 100% of the baseline dose, including, but not limited to, about one-third, about one-half, or about two-thirds of the baseline dose) for a period of time after posaconazole treatment is discontinued. The patient's physiological characteristics include reduced liver enzyme function, particularly reduced CYP3A4 enzyme function (patients are referred to in the art as CYP3A4 intermediate or poor metabolizers), and / or a weight or body fat status described herein. In some embodiments, a patient may have various body fat status characteristics. "Body fat status," "body fat profile," "obesity status," "obesity profile," and derivatives and variations thereof refer to at least seven characteristics (BMI, ideal body weight, waist circumference, body fat percentage, android body fat percentage, dinoid body fat percentage, and total body fat) as described herein. In some embodiments, a body fat status is referred to as obese, and a patient is referred to as obese or an obese patient.

[0138]

[0147] As described herein, the applicant of the present invention has determined that the present invention is applicable to certain patients, i.e., Patients with certain physiological characteristics described, e.g., body fat status, weight status, and / or hepatic metabolic enzyme status, may experience substantially higher posaconazole plasma levels after discontinuing posaconazole treatment and / or may experience a decrease in posaconazole plasma levels that is greater than the known or intended elimination half-life (t ) of posaconazole, e.g., as described on the NOXAFIL label. 1 / 2) exhibit a longer half-life than CYP3A4 substrate drugs, it has been found that after discontinuing posaconazole treatment, a hold-off period as described herein may be required before treatment with a CYP3A4 substrate drug or before prescribing the first treatment with a CYP3A4 substrate drug, or the dose of the CYP3A4 substrate drug may be adjusted (reduced) for a period of time after discontinuing posaconazole treatment, as described herein. The dose adjustment period or level may be greater than the period / amount of deferral or dose reduction established for patients considered "normal" patients. If the plasma levels of posaconazole are substantially higher and / or the expected elimination half-life (t) of posaconazole, e.g., as stated on the label for NOXAFIL, is exceeded, the dose adjustment period or level may be greater than the period / amount of deferral or dose reduction established for patients considered "normal" patients. 1 / 2 Patients who exhibit a longer half-life relative to CYP3A4 or who require a longer delay period, a longer dose adjustment period, or a higher dose adjustment level include, for example, obese patients, e.g., those with one or more of the following characteristics: a BMI of at least about 35, a ratio of body mass to ideal body weight of at least about 150%, a waist circumference of greater than about 42 inches, a body fat percentage of greater than about 40%, an android body fat percentage of greater than about 40%, a dysmorphic body fat percentage of greater than about 40%, or a total body fat of greater than about 40 kg, optionally in combination with impaired hepatic function, e.g., a CYP3A4 intermediate or poor metabolizer. Alternatively, patients who are not obese (e.g., not within the ranges considered obese in terms of the various measures of body fat status described herein, i.e., BMI less than about 35, ideal body weight less than about 150%, waist circumference less than about 42 inches, percent body fat less than about 40%, android body fat less than about 40%, zygotic body fat less than about 40%, and total body fat less than about 40 kg) but who have impaired hepatic metabolic function, e.g., patients considered to be CYP3A4 intermediate or CYP3A4 poor metabolizers, may also, according to the applicants of the present invention, exhibit higher steady-state posaconazole plasma levels and / or a lower posaconazole elimination half-life (t 1 / 2), it may be necessary to allow a longer "drug-free" period (as described herein) after discontinuing posaconazole treatment before initiating treatment with a CYP3A4 substrate. Alternatively, it may be necessary to allow a longer period (known in the art) after discontinuing posaconazole treatment before initiating treatment with a CYP3A4 substrate at a reduced dose (as described herein) from the base dose to minimize or avoid adverse effects, such as QTc prolongation and other side effects of CYP3A4 substrates known in the art. It was previously unknown that patients with the above-described physiological characteristics would require a longer "drug-free" period between doses of posaconazole and a CYP3A4 substrate, or that patients would need to be treated or prescribed a reduced base dose of a CYP3A4 substrate for a period after discontinuing posaconazole, due to the effects of those physiological characteristics on steady-state posaconazole plasma levels and / or elimination half-life.

[0139]

[0148] The activity levels of drug-metabolizing P450 isoenzymes can vary from person to person. Criteria for classifying metabolizers include, but are not limited to, allelic heterogeneity of CYP540 isoenzyme genes. For example, the CYP3A4 gene has allelic heterogeneity, and expression of the CYP3A4*22 allele can be used to classify subjects into CYP3A4 hypoexpressors (i.e., individuals who possess one CYP3A4*22 allele) and CYP3A4 normal expressors (i.e., individuals who do not possess the CYP3A4*22 allele).

[0140]

[0149] In some embodiments, the patient treated by the methods of the present disclosure is a body Body Mass Index (BMI, units are kg / m unless otherwise specified) 2 ) is less than about 25, e.g., less than about 24.5, less than about 24, less than about 23.5, less than about 23, less than about 22.5, less than about 22, less than about 21.5, less than about 21, less than about 20.5, less than about 20, less than about 19.5, about 19, or less than about 18.5, inclusive of all ranges and subranges thereof.

[0141]

[0150] In some embodiments, patients treated by the methods of the present disclosure have a body mass index (BMI, in kg / m unless otherwise defined). 2 ), is at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, Also about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, at least about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, at least about 124, at least about 125, at least about 126, at least about 127, at least about 128, at least about 129, at least about 130, at least about 131, at least about 132, at least about 133, at least about 134, at least about 135, at least about 136, at least about 137, at least about 138, at least about 139, at least about 140, at least about 141, at least about 142, at least about 143, at least about 144, at least about 145, at least about 146, at least about 147, at least about 148, at least about 149, at least about 150, at least about 151, at least about 152,at least about 153, at least about 154, at least about 155, at least about 156, at least about 157, at least about 158, at least about 159, at least about 160, at least about 161, at least about 162, at least about 163, at least about 164, at least about 165, at least about 166, at least about 167, at least about 168, at least about 169, at least about 170, at least about 171, at least about 172, at least about 173, at least about 174, at least about 175, at least about 176, at least about 177, at least about 178, at least about 179, at least about 180, at least about 181, at least about 182, at least about In one embodiment, the patient has a body mass index (BMI) of at least about 35, in kg / m unless otherwise defined, of at least 183, at least about 184, at least about 185, at least about 186, at least about 187, at least about 188, at least about 189, at least about 190, at least about 191, at least about 192, at least about 193, at least about 194, at least about 195, at least about 195, at least about 196, at least about 197, at least about 198, at least about 199, at least about 200, at least about 201, at least about 202, at least about 203, at least about 204, at least about 205, at least about 206, at least about 207, at least about 208, at least about 209, or at least about 210 (including all ranges and subranges thereof). 2 In another embodiment, the patient has a body mass index (BMI) of at least about 40. In another embodiment, the patient has a body mass index (BMI) of at least 50.

[0142]

[0151] In some embodiments, the BMI of a patient treated by the methods of the present invention is: In some embodiments, the patient's BMI is at least about 25 to at least about 29.9, at least about 25.5 to at least about 29, at least about 26 to at least about 28.5, at least about 26.5 to at least about 28, or at least about 27 to at least about 27.5, inclusive of all ranges and subranges, and is considered overweight or pre-obese. or at least about 32 to at least about 32.5 (including all ranges and subranges) is considered obese. In some embodiments, a patient's BMI is at least about 35 to at least about 39.9, at least about 35.5 to at least about 39, at least about 36 to at least about 38.5, at least about 36.5 to at least about 38, or at least about 37 to at least about 37.5 (including all ranges and subranges), and any BMI described herein, is considered obese. In other embodiments, the BMI of a patient treated by the methods of the invention is at least about 35 or greater, 40 or greater, 50 or greater, 60 or greater, 70 or greater, 80 or greater, 90 or greater, 100 or greater, 110 or greater, 120 or greater, 130 or greater, 140 or greater, 150 or greater, 160 or greater, 170 or greater, 180 or greater, 190 or greater, 200 or greater, or 210 or greater (including all ranges and subranges thereof).

[0143]

[0152] In some embodiments, the patient treated by the methods of the present invention has a BMI of A child or adolescent with a BMI between at least about the 85th percentile and at least about the 95th percentile, at least about the 86th percentile and at least about the 94th percentile, at least about the 87th percentile and at least about the 93rd percentile, at least about the 88th percentile and at least about the 92nd percentile, at least about the 89th percentile and at least about the 90th percentile (including all ranges and subranges thereof), and any of the BMI percentiles described herein, is considered overweight or pre-obese. In some embodiments, a patient's BMI is at least about the 95th percentile, at least about the 96th percentile, at least about the 97th percentile, at least about the 98th percentile, at least about the 99th percentile, or at least about the 100th percentile (including all ranges and subranges thereof), and any of the BMI percentiles described herein, is considered obese. In one embodiment, the patient is between about 5 and about 19 years old, or between about 7 and about 18 years old.

[0144]

[0153] In some embodiments, the patient treated by the methods of the present disclosure is in their first trimester of pregnancy. In some embodiments, the patient is a female patient in the first to third trimester of pregnancy with a BMI of at least 25 to at least about 29.9, at least about 25.5 to at least about 29, at least about 26 to at least about 28.5, at least about 26.5 to at least about 28, or at least about 27 to at least about 27.5, inclusive of all ranges and subranges, and is considered overweight or pre-obese. In some embodiments, the patient is a female patient in the first to third trimester of pregnancy with a BMI of at least about 30 to at least about 34.9, at least about 30.5 to at least about 34, at least about 31 to at least about 33.5, at least about 31.5 to at least about 33, or at least about 32 to at least about 32.5, inclusive of all ranges and subranges, and is considered obese. In some embodiments, the patient treated by the methods of the present disclosure is a female patient in the first, second, or third trimester of pregnancy and has a BMI of at least about 35 to at least about 39.9, at least about 35.5 to at least about 39, at least about 36 to at least about 38.5, at least about 36.5 to at least about 38, at least about 37 to at least about 37.5 (including all ranges and subranges thereof) and is considered severely obese.

[0145]

[0154] In some embodiments, the BMI is calculated as weight (in kg) / (me height in knots) 2 , weight in pounds / (height in inches) 2 703, but is not limited to these.

[0146]

[0155] In some embodiments, the patient treated by the methods of the present disclosure may alternatively , at least about 110%, at least about 111%, at least about 112%, at least about 113%, at least about 114%, at least about 115%, at least about 116%, at least about 117%, at least about 118%, at least about 119%, at least about 120 %, at least about 121%, at least about 122%, at least about 123%, at least about 124%, at least about 125%, at least about 126%, at least about 127%, at least about 128%, at least about 129%, at least about 130%, at least about 131%, at least about 132%, at least about 133%, at least about 134%, at least about 135%, at least about 136%, at least about 137%, at least about 138%, at least about 139%, at least about 140%, at least about 141%, at least about 142%, at least about Also about 143%, at least about 144%, at least about 145%, at least about 146%, at least about 147%, at least about 148%, at least about 149%, at least about 150%, at least about 151%, at least about 152%, at least about 153%, at least about 154%, at least about 155%, at least about 156%, at least about 157%, at least about 158%, at least about 159%, at least about 160%, at least about 161%, at least about 162%, at least about 163%, at least about 164%, at least about 165 , at least about 166%, at least about 167%, at least about 168%, at least about 169%, at least about 170%, at least about 171%, at least about 172%, at least about 173%, at least about 174%, at least about 175%, at least about 176%, at least about 177%, at least about 178%, at least about 179%, at least about 180%, at least about 181%, at least about 182%, at least about 183%, at least about 184%, at least about 185%, at least about 186%, at least about 187%, at least about 188%, at least about 189%, at least about 200%, at least about 201%, at least about 202%, at least about 203%, at least about 204%, at least about 205%, at least about 206%, at least about 207%, at least about 208%, at least about 209%, at least about 210%, at least about 211%, at least about 212%, at least about 213%, at least about 214%, at least about 215%, at least about 216%, at least about 217%, at least about 218%, at least about 219%, at least about 220%, at least about 221%, at least about 222%, at least about 223%, at least about 224%, at least about 225%, at least about 226%, at least about 227%, at least about 228%, at least about 229%, at least about 230%, at least about 231%, at least about 232%, at least about 233%, at least about 234%, at least about 235%, at least about 236%, at least about 237%, at least about 238%, at least about 2 about 188%, at least about 189%, at least about 190%, at least about 191%, at least about 192%, at least about 193%, at least about 194%, at least about 195%, at least about 196%, at least about 197%, at least about 198%, at least about 199%, at least about 200%, at least about 201%, at least about 202%, at least about 203%, at least about 204%, at least about 205%, at least about 206%, at least about 207%, at least about 208%, at least about 209%, at least about 210%,at least about 211%, at least about 212%, at least about 213%, at least about 214%, at least about 215%, at least about 216%, at least about 217%, at least about 218%, at least about 219%, at least about 220%, at least about 221%, at least about 222%, at least about 223%, at least about 224%, at least about 225%, at least about 226%, at least about 227%, at least about 228%, at least about 229%, at least about at least about 230%, at least about 231%, at least about 232%, at least about 233%, at least about 234%, at least about 235%, at least about 236%, at least about 237%, at least about 238%, at least about 239%, at least about 240%, at least about 241%, at least about 242%, at least about 243%, at least about 244%, at least about 245%, at least about 246%, at least about 247%, at least about 248%, at least about 249%, at least about 300%, at least about 301%, at least about 302%, at least about 303%, at least about 304%, at least about 305%, at least about 306%, at least about 307%, at least about 308%, at least about 309%, at least about 310%, at least about 311%, at least about 312%, at least about 313%, at least about 314%, at least about 315%, at least about 316%, at least about 317%, at least about 318%, at least about 319%, at least about 320%, at least about 321%, at least about 322%, at least about 323%, at least about 324%, at least about 325%, at least about 326%, at least about 327%, at least about 328%, at least about 329%, at least about 400%, at least about 401%, at least about 402%, at least about 403%, at least about 404%, at least about 405%, at least about 406%, at least about 407%, at least about 408%, at least about 409%, at least about 410%, at least about 411%, at least about 412%, at least about 413 about 249%, at least about 250%, at least about 251%, at least about 252%, at least about 253%, at least about 254%, at least about 255%, at least about 256%, at least about 257%, at least about 258%, at least about 259%, at least about 260%, at least about 261%, at least about 262%, at least about 263%, at least about 264%, at least about 265%, at least about 266%, at least about 267%, at least about 268%, at least about 269%, at least about 300%, at least about 301%, at least about 302%, at least about 303%, at least about 304%, at least about 305%, at least about 306%, at least about 307%, at least about 308%, at least about 309%, at least about 409%, at least about 410%, at least about 411%, at least about 412%, at least about 413%, at least about 414%, at least about 415%, at least about 416%, at least about 417%, at least about 418%, at least about 419%, at least about 420%, at least about 421%, at least about 422%, at least about 423%, at least about 424%, at least about 425%, at least about 426%, at least about 427%, at least about 428%, at least about 429%, at least about 430%, at least about 431%, at least about 432%, at least about 433%, at least about 434%, at least about 435%, at least about 436%, at least about 437%, at least about 438%, at least about 439%, at least about 440%, at least about 441%, at The patient may also be described as having a % ideal body weight (%IBW) of at least about 68%, at least about 269%, at least about 270%, at least about 271%, at least about 272%, at least about 273%, at least about 274%, at least about 275%, at least about 276%, at least about 277%, at least about 278%, at least about 279%, or at least about 280%, including all ranges and subranges thereof, and any of the % ideal body weight (%IBW) ratios described herein. In one embodiment, the patient has a % ideal body weight (IBW) of at least about 150%. In one embodiment, the patient has a % ideal body weight (IBW) of at least about 250%. In another embodiment, the patient has a % ideal body weight (IBW) of at least 150% and can be considered obese.

[0147]

[0156] In some embodiments, patients treated according to the present disclosure have a mean body mass of over about 32 inches. , greater than about 33 inches, greater than about 34 inches, greater than about 35 inches, greater than about 36 inches, greater than about 37 inches, greater than about 38 inches, greater than about 39 inches, greater than about 40 inches, greater than about 41 inches, greater than about 42 inches, greater than about 43 inches, greater than about 44 inches, greater than about 45 inches, greater than about 46 inches, greater than about 47 inches, greater than about 48 inches, greater than about 49 inches, greater than about 50 inches, greater than about 51 inches, greater than about 52 inches, greater than about 53 inches, greater than about 54 inches, greater than about 55 inches, greater than about 56 inches, greater than about 57 inches, greater than about 58 inches, greater than about 59 inches, greater than about 60 inches, greater than about 61 inches, greater than about 62 inches, greater than about 63 inches, greater than about 64 inches, greater than about 65 inches (including all ranges and subranges thereof), and any waist size or waist circumference described herein. In one embodiment, a patient having a waist size or waist circumference of about 42 inches is considered obese. In another embodiment, the patient has a waist size or waist circumference of greater than about 48 inches. In another embodiment, the patient has a waist size or waist circumference of at least 42 inches.

[0148]

[0157] In some embodiments, about 20% of patients treated with the methods of the present disclosure The patient may also be described as having a body fat percentage of greater than about 21%, greater than about 22%, greater than about 23%, greater than about 24%, greater than about 25%, greater than about 26%, greater than about 27%, greater than about 28%, greater than about 29%, greater than about 30%, greater than about 31%, greater than about 32%, greater than about 33%, greater than about 34%, greater than about 35%, greater than about 36%, greater than about 37%, greater than about 38%, greater than about 39%, greater than about 40%, greater than about 41%, greater than about 42%, greater than about 43%, greater than about 44%, greater than about 45%, greater than about 46%, greater than about 47%, greater than about 48%, greater than about 49%, or greater than about 50%, inclusive of all ranges and subranges thereof, and any body fat percentage described herein. In one embodiment, the patient's body fat percentage is greater than about 40%. In one embodiment, the patient's body fat percentage is at least about 50%. In other embodiments, a patient is considered obese if their body fat percentage is greater than about 40%. In some embodiments, methods for calculating body fat percentage include, but are not limited to, expressing total body fat as a percentage of total body weight. Other criteria for determining obesity can also be used. For example, the American Council on Exercise defines "average" body fat percentage as about 25-31% for women and about 18-24% for men, with obese women defined as about 32% or greater and obese men defined as about 25% or greater.

[0149]

[0158] In other embodiments, the patient may alternatively have greater than about 30%, greater than about 31%, greater than about 3 More than 2%, more than about 33%, more than about 34%, more than about 35%, more than about 36%, more than about 37%, more than about 38%, more than about 39%, more than about 40%, more than about 41%, more than about 42%, more than about 43%, more than about 44%, more than about 45%, more than about 46%, about 47% Very, more than about 48%, more than about 49%, more than about 50%, more than about 51%, more than about 52%, more than about 53%, more than about 54%, more than about 55%, more than about 56%, more than about 57%, more than about 58%, more than about 59%, more than about 60%, more than about 61%, more than about 62%, They may also be described as having an android body fat percentage of greater than about 63%, greater than about 64%, greater than about 65%, greater than about 66%, greater than about 67%, greater than about 68%, greater than about 69%, greater than about 70%, greater than about 71%, greater than about 72%, greater than about 73%, greater than about 74%, greater than about 75%, greater than about 76%, greater than about 77%, greater than about 78%, greater than about 79%, or greater than about 80% (including all ranges and subranges thereof), as well as any android body fat percentage described herein. In one embodiment, a patient may be considered obese if they have an android body fat percentage greater than about 40%. In one embodiment, a patient may be considered obese if they have an android body fat percentage greater than about 50%.

[0150]

[0159] In other embodiments, the patient may alternatively have at least about 30% at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39%, at least about 40%, at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49%, at least about 50%, at least about The android-type body fat percentage may also be described as having about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, or at least about 80% (including all ranges and subranges), and any android-type body fat percentage described herein. In one embodiment, the patient has an android-type body fat percentage of at least about 50%.

[0151]

[0160] In other embodiments, the patient may alternatively have greater than about 30%, greater than about 31%, greater than about 3 More than 2%, more than about 33%, more than about 34%, more than about 35%, more than about 36%, more than about 37%, more than about 38%, more than about 39%, more than about 40%, more than about 41%, more than about 42%, more than about 43%, more than about 44%, more than about 45%, more than about 46%, about 47 More than %, more than about 48%, more than about 49%, more than about 50%, more than about 51%, more than about 52%, more than about 53%, more than about 54%, more than about 55%, more than about 56%, more than about 57%, more than about 58%, more than about 59%, more than about 60%, more than about 61%, about 62% A patient may also be described as having a ginoid body fat percentage of greater than about 63%, greater than about 64%, greater than about 65%, greater than about 66%, greater than about 67%, greater than about 68%, greater than about 69%, greater than about 70%, greater than about 71%, greater than about 72%, greater than about 73%, greater than about 74%, greater than about 75%, greater than about 76%, greater than about 77%, greater than about 78%, greater than about 79%, or greater than about 80% (including all ranges and subranges thereof), as well as any ginoid body fat percentage described herein. In one embodiment, a patient with a ginoid body fat percentage greater than about 40% can be considered obese. In one embodiment, a patient with a % ginoid body fat greater than about 50% can be considered obese.

[0152]

[0161] In other embodiments, the patient may alternatively weigh more than about 30 kg, more than about 31 kg, or Over 32kg, over 33kg, over 34kg, over 35kg, over 36kg, over 37kg, over 38kg, over 39kg, over 40kg, over 41kg, over 42kg, over 43kg , over 44kg, over 45kg, over 46kg, over 47kg, over 48kg, over 49kg, over 50kg, over 51kg, over 52kg, over 53kg, over 54kg, over 55k More than 56kg, more than 57kg, more than 58kg, more than 59kg, more than 60kg, more than 61kg, more than 62kg, more than 63kg, more than 64kg, more than 65kg, more than 66kg, more than 66kg More than 7kg, more than about 68kg, more than about 69kg, more than about 70kg, more than about 71kg, more than about 72kg, more than about 73kg, more than about 74kg, more than about 75kg, more than about 76kg, more than about 77kg, more than about 78kg, A total body fat of greater than about 79 kg, greater than about 80 kg, greater than about 81 kg, greater than about 82 kg, greater than about 83 kg, greater than about 84 kg, greater than about 85 kg, greater than about 86 kg, greater than about 87 kg, greater than about 88 kg, greater than about 89 kg, greater than about 90 kg, greater than about 91 kg, greater than about 92 kg, greater than about 93 kg, greater than about 94 kg, greater than about 95 kg, greater than about 96 kg, greater than about 97 kg, greater than about 98 kg, greater than about 99 kg, greater than about 100 kg, at least 101 kg, at least 102 kg, at least 103 kg, at least 104 kg, at least 105 kg, at least 106 kg, at least 107 kg, at least 108 kg, at least 109 kg, or at least 110 kg (including all ranges and subranges thereof), and any of the total body fats described herein, in one embodiment, a patient can be considered obese if they have a total body fat of greater than about 40 kg. In one embodiment, a patient can be considered obese if they have more than about 50 kg of total body fat.

[0153]

[0162] In other embodiments, the obesity condition of the patient treated by the methods of the present disclosure is: In another embodiment, the obesity status of the patient can be measured by skinfold thickness. In another embodiment, the obesity status of the patient can be measured by skinfold thickness. In other embodiments, the obesity status of a patient can be measured by electrical impedance. In other embodiments, the obesity status of a patient can be measured by hydroweighing or densitometry. In other embodiments, the obesity status of a patient can be measured by air displacement. In other embodiments, the obesity status of a patient can be measured by dilution or densitometry. In other embodiments, the obesity status of a patient can be measured by dual energy X-ray absorptiometry. In other embodiments, the obesity status of a patient can be measured by computed tomography and magnetic resonance imaging. In some embodiments, when using the methods described herein, clinical criteria, conventional criteria, and / or criteria approved by the World Health Organization and the Centers for Disease Control and Prevention (CDC) are not used. The obesity state may be defined, but is not limited to, using criteria published by the WHO and the WHO (both of which are incorporated herein by reference in their entireties for all purposes). For example, the WHO defines obesity as a BMI of 30 or greater and overweight as a BMI of 25 or greater (less than 30). Similarly, the CDC defines a BMI of 18.5 to less than 25 as normal, 25.0 to less than 30 as overweight, and 30.0 or greater as obese. The CDC further subdivides obesity into three classes: Class 1 for BMI 30 to less than 35, Class 2 for BMI 35 to less than 40, and Class 3 for BMI 40 or greater. The CDC sometimes refers to Class 3 obesity as "extreme" or "severe" obesity.

[0154]

[0163] In some embodiments, the patient treated by the methods of the present disclosure is For example, the patient may have two or more of the physiological characteristics described herein. For example, the patient has a BMI of at least about 35 and a relative ideal body weight of at least 150%. In some embodiments, the patient has a BMI of at least about 35 and a waist size of greater than about 42 inches. In some embodiments, the patient has a BMI of at least about 35 and a body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35 and an android body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35 and a dynoid body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35 and a total body fat of greater than about 40 kg. In various other embodiments, the patient may have a combination of any two or more of the specific physiological indices described herein.

[0155]

[0164] In some embodiments, the patient has three or more physiological indices described herein. For example, the patient may have a BMI of at least about 35, a relative to ideal body weight of at least 150%, and a waist size of greater than about 42 inches. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, and a body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, and a android body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, and a dynoid body fat percentage of greater than about 40%. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, and a total body fat of greater than about 40 kg. In various other embodiments, the patient may have a combination of any three or more of the specific physiological indices described herein.

[0156]

[0165] In some embodiments, the patient has four or more physiological indices described herein. For example, the patient may have a BMI of at least about 35, a ratio of ideal body weight to at least 150%, a waist size greater than about 42 inches, and a body fat percentage greater than about 40%. In some embodiments, the patient may have a BMI of at least about 35, a ratio of ideal body weight to at least 150%, a waist size greater than about 42 inches, and a female body fat percentage greater than about 40%. In some embodiments, the patient may have a BMI of at least about 35, a ratio of ideal body weight to at least 150%, a waist size greater than about 42 inches, and a female body fat percentage greater than about 40%. In some embodiments, the patient may have a BMI of at least about 35, a ratio of ideal body weight to at least 150%, a waist size greater than about 42 inches, and a total body fat percentage greater than about 43 kg. In some embodiments, the patient may have a BMI of at least about 35, a ratio of ideal body weight to at least 150%, a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and a female body fat percentage greater than about 40%. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and a zygotic body fat percentage greater than about 40%. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and a total body fat greater than about 40 kg. In some embodiments, the patient has a BMI of at least about 35, a relative to ideal body weight of at least 150%, a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and a zygotic body fat percentage greater than about 40%, and a total body fat greater than about 40 kg. In one embodiment, the patient has a BMI of at least about 35, a relative ideal body weight of at least 150%, a waist size of greater than about 42 inches, a body fat percentage of greater than about 40%, an android body fat percentage of greater than about 40%, a dynoid body fat percentage of greater than about 40%, and a total body fat of greater than about 40 kg. In various other embodiments, the patient may have a combination of some or all of the specific physiological indices described herein.

[0157]

[0166] In some embodiments, the patient has a waist size of greater than about 42 inches and body fat In some embodiments, the patient has a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and an android body fat percentage greater than about 40%. In some embodiments, the patient has a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and an android body fat percentage greater than about 40%. In some embodiments, the patient has a waist size greater than about 42 inches, a body fat percentage greater than about 40%, and a total body fat greater than about 40 kg.

[0158]

[0167] In some embodiments, the patient has a body fat percentage of greater than about 40% and an android body type. and a body fat percentage greater than about 40%, and a dynoid body fat percentage greater than about 40%. In some embodiments, the patient has a body fat percentage greater than about 40%, an android body fat percentage greater than about 40%, and a total body fat greater than about 40 kg. In some embodiments, the patient has a body fat percentage greater than about 40%, a dynoid body fat percentage greater than about 40%, and a total body fat greater than about 40 kg. In some embodiments, the patient has an android body fat percentage greater than about 40%, a dynoid body fat percentage greater than about 40%, and a total body fat greater than about 43 kg. In some embodiments, the patient may have any combination of the obesity characteristics described herein.

[0159]

[0168] In some embodiments, a subject has at least one obesity trait described herein. In some embodiments, a patient having at least one obesity trait described herein is a CYP3A4 intermediate metabolizer. In some embodiments, a patient having at least one obesity trait described herein is a CYP3A4 poor metabolizer. In some embodiments, a patient having at least one obesity trait described herein is a CYP3A4 normal metabolizer. In other further embodiments, a patient is not obese, e.g., has a normal weight, but is a CYP3A4 intermediate metabolizer or a CYP3A4 poor metabolizer.

[0160]

[0169] Alternatively, in some embodiments, the CYP3A4 genotype is determined by the target barrier In some embodiments, CYP3A4 genotype can be tested using sequence analysis of selected exons.

[0161]

[0170] In various embodiments, the present disclosure further provides a method for treating a patient who has previously been treated with posaconazole. Disclosed is a method of treating a patient with a CYP3A4 substrate drug that is prohibited for use in combination with a strong CYP3A4 inhibitor, e.g., posaconazole, wherein the CYP3A4 substrate drug has an AUC that is about 3000% or less of the normal baseline AUC (see definition above) of the CYP3A4 substrate drug, e.g., about 2950% or less, about 2900% or less, about 2850% or less, about 2800% or less of the normal baseline AUC of the CYP3A4 substrate drug. % or less, about 2750% or less, about 2700% or less, about 2650% or less, about 2600% or less, about 2550% or less, about 2500% or less, about 2450% or less, about 2400% or less, about 2350% or less, about 2300 % or less, about 2250% or less, about 2200% or less, about 2150% or less, about 2100% or less, about 2050% or less, about 2000% or less, about 1950% or less, about 1900% or less, about 1850% or less, about 1800 % or less, about 1750% or less, about 1700% or less, about 1650% or less, about 1600% or less, about 1550% or less, about 1500% or less, about 1450% or less, about 1400% or less, about 1350% or less, about 1300% or less, about 1250% or less Approx. 1200% or less, approx. 1150% or less, approx. 1100% or less, approx. 1050% or less, approx. 1000% or less, approx. 950% or less, approx. 900% or less, approx. 0% or less, about 550% or less, about 500% or less, about 450% or less, about 445% or less, about 440% or less, about 435% or less, 430% or less, about 425% or less, about 420% or less, about 415% or less, about 410% or less, about 405% or less, about 400% or less, about 395% or less, about 390% or less, about 385% or less, about 380% or less, about 375% or less, about 370% or less, about 365% or less, about 360% or less, about 355% or less, about 350% or less, about 345% or less, about 340% or less, about 3 35%, 330% or less, about 325% or less, about 320% or less, about 315% or less, about 310% or less, about 305% or less, or about 300% or less, about 295% or less, about 290% or less, about 285% or less, about 280% or less, about 275% or less, about 270% or less, about 265% or less, about 260% or less, about 255% or less, about 250% or less, about 245% or less, about 240% or less, about 235% or less, 230% or less, about 225% or less, about 220% or less, about 216% or less, about 215% or less, about 21 or about 100% or less, including all ranges and subranges thereof. In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is maintained at a level of about 150% or less of the normal baseline AUC of ranolazine. As used herein, "normal baseline AUC of ranolazine" refers to the steady-state AUC measured for a particular dose of ranolazine in the absence of other drugs. 0-12In some embodiments, the steady-state AUC 0-12 The (%CV) measured after administration of 500 mg of ranolazine is 13,720 (67.0%) ng*h / mL. In some embodiments, the steady-state AUC 0-12 The %CV measured after administration of 1000 mg of ranolazine is 32,091 (42.2%) ng*h / mL. In another specific embodiment, the CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is maintained at a level that is about 216% or less of the normal baseline AUC of lurasidone. As used herein, "normal baseline AUC of lurasidone" refers to the mean AUC measured for a particular dose of lurasidone in the absence of other drugs. 0-tau In some embodiments, the mean AUC 0-tau is approximately 743 ng*h / mL as measured after administration of 120 mg of lurasidone with a 350 kcal meal. In another specific embodiment, the CYP3A4 drug is tadalafil, and the AUC of tadalafil is maintained at a level that is no greater than about 410% of the normal baseline AUC of tadalafil. As used herein, "normal baseline AUC of tadalafil" refers to the mean AUC measured for a particular dose of tadalafil in the absence of other drugs. 0-∞ (% CV) are shown. In some embodiments, the mean AUC 0-∞ (%CV) is about 3647 (34.0%) μg*h / L measured after administration of 10 mg of tadalafil. 0-∞ (%CV) is about 13,006 (43.9%) μg*h / L for 20 mg of tadalafil. 0-∞ The %CV is about 7,000 to about 13,000 (40.0%) μg*h / L for 20 mg of tadalafil. In another specific embodiment, the CYP3A4 substrate drug is erlotinib, and the AUC of erlotinib is maintained at a level of about 164% or less of the normal baseline AUC of erlotinib at 150 mg. As used herein, "normal baseline AUC of erlotinib" refers to the mean AUC measured for a particular dose of erlotinib in the absence of other drugs.0-24 In some embodiments, the mean AUC 0-24 The %CV was approximately 15.2 (400.0%) μg*h / mL measured after 150 mg of erlotinib. AUC of erlotinib 0-24 The mean AUC (% CV) can vary widely and tends to be increased in cancer patients compared to healthy volunteers. Thus, in some embodiments, the mean AUC 0-24(%CV) is in the range of about 1 μg*h / mL to about 35 μg*h / mL, for example, about 2 μg*h / mL, about 3 μg*h / mL, about 4 μg*h / mL, about 5 μg*h / mL, about 6 μg*h / mL, about 7 μg*h / mL, about 8 μg*h / mL, about 9 μg*h / mL, about 10 μg*h / mL, about 11 μg*h / mL, about 12 μg*h / mL, about 13 μg*h / mL, about 14 μg*h / mL, about 15 μg* h / mL, approximately 16μg*h / mL, approximately 17μg*h / mL, approximately 18μg*h / mL, approximately 19μg*h / mL, approximately 20μg*h / mL, approximately 21μg*h / mL, approximately 22μg*h / mL, approximately 23μg* h / mL, approximately 24μg*h / mL, approximately 25μg*h / mL, approximately 26μg*h / mL, approximately 27μg*h / mL, approximately 28μg*h / mL, approximately 29μg*h / mL, approximately 30μg*h / mL, approximately 31μg* h / mL, approximately 32μg*h / mL, approximately 33μg*h / mL, approximately 34μg*h / mL, approximately 35μg*h / mL, approximately 36μg*h / mL, approximately 37μg*h / mL, approximately 38μg*h / mL, approximately 39μg* h / mL, approximately 40μg*h / mL, approximately 41μg*h / mL, approximately 42μg*h / mL, approximately 43μg*h / mL, approximately 44μg*h / mL, approximately 45μg*h / mL, approximately 46μg*h / mL, approximately 47μg* h / mL, about 48 μg*h / mL, about 49 μg*h / mL, about 50 μg*h / mL, about 51 μg*h / mL, about 52 μg*h / mL, about 53 μg*h / mL, about 54 μg*h / mL, about 55 μg*h / mL, about 56 μg*h / mL, about 57 μg*h / mL, about 58 μg*h / mL, about 59 μg*h / mL, about 60 μg*h / mL, inclusive of all ranges and subranges thereof. In another specific embodiment, the CYP3A4 substrate drug is solifenacin succinate, and the AUC of solifenacin succinate is maintained at a level that is about 270% or less of the normal baseline AUC of solifenacin succinate. As used herein, "usual baseline AUC of solifenacin succinate" refers to the mean AUC measured for a particular dose of solifenacin succinate in the absence of other drugs. 0-24 In some embodiments, the mean AUC 0-24(%CV) is about 463 (37%) ng*h / mL for 5 mg solifenacin succinate. In some embodiments, the mean AUC 0-24 The %CV is about 749 (22%) ng*h / mL for 10 mg solifenacin succinate. In another specific embodiment, the CYP3A4 drug is everolimus, and the AUC of everolimus is maintained at a level that is about 440% or less of the normal baseline AUC of everolimus. As used herein, "normal baseline AUC of everolimus" refers to the mean AUC measured at steady-state conditions for a particular dose of everolimus in the absence of other drugs. 0-24 Shown are ±SD. In some embodiments, the mean AUC 0-24 ±SD is approximately 536 ± 7.7 ng*h / L measured after administration of everolimus 10 mg.

[0162]

[0171] In various other embodiments, the present disclosure provides a method for treating a patient who has previously been treated with posaconazole. Disclosed herein are methods of treating a patient, the method comprising administering or prescribing a reduced dose (e.g., about 10% to 90% of the reference dose) of a CYP3A4 substrate drug that is prohibited for use in combination with a strong CYP3A4 inhibitor, for about 2 to 42 days after discontinuing posaconazole treatment, wherein the CYP3A4 substrate drug has an AUC of about 3000% or less of the CYP3A4 substrate drug's normal baseline AUC (see definition above), e.g., about 2950% or less, about 2900% or less, or about 2850% or less of the CYP3A4 substrate drug's normal baseline AUC. , about 2800% or less, about 2750% or less, about 2700% or less, about 2650% or less, about 2600% or less, about 2550% or less, about 2500% or less, about 2450% or less, approximately 2400% or less, approximately 2350% or less, approximately 2300% or less, approximately 2250% or less, approximately 2200% or less, approximately 2150% or less, approximately 21 00% or less, approximately 2050% or less, approximately 2000% or less, approximately 1950% or less, approximately 1900% or less, approximately 1850% or less, approximately 1800% or less, approximately 1750 % or less, approximately 1700% or less, approximately 1650% or less, approximately 1600% or less, approximately 1550% or less, approximately 1500% or less, approximately 1450% or less, approximately 1400% or lessLower, about 1350% or less, about 1300% or less, about 1250% or less, about 1200% or less, about 1150% or less, about 1100% or less, about 1050% or less, about 1000% or less, about 950% or less, about 900% or less, about 850 % or less, about 800% or less, about 750% or less, about 700% or less, about 650% or less, about 600% or less, about 550% or less, about 500% or less, about 450% or less, about 445% or less, about 440% or less, about 435% or less, 43 0% or less, approximately 425% or less, approximately 420% or less, approximately 415% or less, approximately 410% or less, approximately 405% or less, approximately 400% or less, approximately 395% or less, approximately 390% or less, approximately 385% or less, approximately 380% or less, approximately 375% or less, 370% or less, about 365% or less, about 360% or less, about 355% or less, about 350% or less, about 345% or less, about 340% or less, about 335% or less, 330% or less, about 325% or less, about 320% or less, about 315% or less, Approx. 310% or less, approx. 305% or less, approx. 300% or less, approx. 295% or less, approx. 290% or less, approx. 285% or less, approx. 280% or less, approx. Lower, about 250% or less, about 245% or less, about 240% or less, about 235% or less, 230% or less, about 225% or less, about 220% or less, about 216% or less, about 215% or less, about 210% or less, about 205% or less, about 200% or less, about 195% or less, about 190% or less, about 185% or less, about 180% or less, about 175% or less, about 170% or less, about 165% or less, about 160% or less, about 155% or less, about 150% or less, about 145% or less, about 140% or less, about 135% or less, 130% or less, about 125% or less, about 120% or less, about 115% or less, about 110% or less, about 105% or less, or about 100% or less (including all ranges and subranges thereof). In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is maintained at a level of about 150% or less of the normal baseline AUC of ranolazine. In another specific embodiment, the CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is maintained at a level of about 216% or less of the normal baseline AUC of lurasidone. In another specific embodiment, the CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is maintained at a level that is about 410% or less of the normal baseline AUC of tadalafil.In another specific embodiment, the CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is maintained at a level of about 260% or less of the normal baseline AUC of tadalafil. In another specific embodiment, the CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is maintained at a level of about 207% or less of the normal baseline AUC of tadalafil. In another specific embodiment, the CYP3A4 substrate drug is erlotinib, and the AUC of erlotinib is maintained at a level of about 164% or less of the normal baseline AUC of erlotinib. In another specific embodiment, the CYP3A4 substrate drug is solifenacin succinate, and the AUC of solifenacin succinate is maintained at a level of about 270% or less of the normal baseline AUC of solifenacin succinate. In another specific embodiment, the CYP3A4 substrate drug is everolimus, and the AUC of everolimus is maintained at a level that is no greater than about 440% of the normal baseline AUC of everolimus.

[0163]

[0172] In various embodiments, the present disclosure further provides a method for treating a patient who has previously been treated with posaconazole. Disclosed is a method of treating a patient with a CYP3A4 substrate drug that is prohibited for use in combination with a strong CYP3A4 inhibitor, such as posaconazole, and the CYP3A4 substrate drug is C max The usual baseline C max approximately 4000% or less of the normal baseline C maxAbout 3950% or less, about 3900% or less, about 3850% or less, about 3800% or less, about 3750% or less, about 3700% or less, about 3650% or less, about 3600% or less, about 3550% or less, about 3500% or less, about 3450% or less, about 3400% or less, about 3350% or less, about 3300% or less, about 3250% or less, about 3200% or less, about 3150% or less, about 3100% or less, about 3050% or less less than about 3000%, less than about 2950%, less than about 2900%, less than about 2850%, less than about 2800%, less than about 2750%, less than about 2700%, less than about 2650%, less than about 2600%, less than about 2550%, less than about 2500%, less than about 2450%, less than about 2400%, less than about 2350%, less than about 2300%, less than about 2250%, less than about 2200%, less than about 2150%, less than about 2100% or more Lower, about 2050% or less, about 2000% or less, about 1950% or less, about 1900% or less, about 1850% or less, about 1800% or less, about 1750% or less, about 1700% or less, about 1650% or less, about 1600% or less, about 1550% or less, about 1500% or less, about 1450% or less, approx. 1400% or less, approx. 1350% or less, approx. 1300% or less, approx. 1250% or less, approx. 1200% or less, approx. 1150% or less, approx. Lower, about 800% or less, about 750% or less, about 700% or less, about 650% or less, about 600% or less, about 550% or less, about 500% or less, about 450% or less, about 445% or less, about 440% or less, about 435% or less, 430% or less, about 425% or less, about 420% or less Lower, about 415% or less, about 410% or less, about 405% or less, about 400% or less, about 395% or less, about 390% or less, about 385% or less, about 380% or less, about 375% or less, about 370% or less, about 365% or less, about 360% or less, about 355% or less, about 350% Below, about 345% or less, about 340% or less, about 335% or less, 330% or less, about 325% or less, about 320% or less, about 315% or less, about 310% or less, about 305% or less, about 300% or less, about 295% or less, about 290% or less, about 285% or less, about 280% Below, about 275% or less, about 270% or less, about 265% or less, about 260% or less, about 255% or less, about 250% or less, about 245% or less, about 240% or less, about 235% or less, 230% or less, about 225% or less, about 220% or less, about 216% or less, about 215% or less, about 210% or less, e.g., about 210% or less, about 205% or less, about 200% or less, about 195% or less, 190% or less, about 185% or less, about 180% or less, about 175% or less, about 170% or less, 165% or less, about 160% or less, about 155% or less, about 150% or less, about 145% or less, about 140% or less, about 135% or less, about 130% or less, about 125% or less, about 120% or less, about 115% or less, about 110% or less, about 105% or less, or about 100% or less (including all ranges and subranges). In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the C of ranolazine is maintained at about 100% or less (including all ranges and subranges). max is the normal baseline C maxAs used herein, "normal baseline C of ranolazine" refers to maintaining a level of about 150% or less of the normal baseline C of ranolazine. max " is the steady-state C measured for a specific dose of ranolazine in the absence of other drugs. max In some embodiments, the steady-state C max The (%CV) measured after administration of 500 mg of ranolazine is 1081 (49.1%) ng / mL. max The % CV is 1955 (54.0%) ng / mL measured after administration of 1000 mg of ranolazine. In another specific embodiment, the CYP3A4 substrate drug is lurasidone, and the C max is the normal baseline C max As used herein, "lurasidone's normal baseline C max " is the mean C measured for a specific dose of lurasidone in the absence of other drugs. max In some embodiments, the average C max The %CV is about 160 ng / mL when measured after 120 mg of lurasidone administered with a 350 kcal meal. In another specific embodiment, the CYP3A4 substrate drug is tadalafil, and the C max is the normal baseline C max As used herein, "normal baseline C of tadalafil" refers to a level of tadalafil that is maintained at or below about 120% of the normal baseline C of tadalafil. max " is the mean C measured for a specific dose of tadalafil in the absence of other drugs. max In some embodiments, the average C max (%CV) is about 190 (21.7%) μg / L as measured after administration of 10 mg of tadalafil. max The %CV is about 548 (24.0%) μg / L measured after administration of 20 mg of tadalafil. In another specific embodiment, the CYP3A4 substrate drug is erlotinib, and the C max is the usual baseline Cmax As used herein, "normal baseline C of erlotinib" refers to maintaining a C of about 167% or less of normal baseline C of erlotinib. max " is the mean C measured for a specific dose of erlotinib in the absence of other drugs. max In some embodiments, the mean C at steady state max The %CV measured after 150 mg of erlotinib is 1.7 (90%) μg / mL. max can vary widely and tends to be increased in cancer patients compared to healthy volunteers. Thus, in some embodiments, the average AUC 0-24 (%CV) is in the range of about 1 μg*h / mL to about 35 μg*h / mL, for example, about 2 μg*h / mL, about 3 μg*h / mL, about 4 μg*h / mL, about 5 μg*h / mL, about 6 μg*h / mL, about 7 μg*h / mL, about 8 μg*h / mL, about 9 μg*h / mL, about 10 μg*h / mL, about 11 μg*h / mL, about 12 μg*h / mL, about 13 μg*h / mL, about 14 μg*h / mL, about 15 μg*h / mL, about 16 μg*h / mL, about 17 μg*h / mL, about 18 μg* h / mL, about 19 μg*h / mL, about 20 μg*h / mL, about 21 μg*h / mL, about 22 μg*h / mL, about 23 μg*h / mL, about 24 μg*h / mL, about 25 μg*h / mL, about 26 μg*h / mL, about 27 μg*h / mL, about 28 μg*h / mL, about 29 μg*h / mL, about 30 μg*h / mL, about 31 μg*h / mL, about 32 μg*h / mL, about 33 μg*h / mL, about 34 μg*h / mL, including all ranges and subranges thereof. In another specific embodiment, the CYP3A4 substrate drug is solifenacin succinate, and the C max is the normal baseline C max As used herein, "normal baseline C of solifenacin succinate" refers to a level that is maintained at or below about 150% of the normal baseline C of solifenacin succinate. max " is the mean C measured for a specific dose of solifenacin succinate in the absence of other drugs. max In some embodiments, the mean C measured after administration of 5 mg solifenacin succinate ismax (%CV) is 24.01 (30%) ng / mL. In some embodiments, the mean C measured after administration of 10 mg solifenacin succinate max In another specific embodiment, the CYP3A4 drug is everolimus, and the C max is the normal baseline C max As used herein, "normal baseline C of everolimus" refers to maintaining a C of about 200% or less of the normal baseline C of everolimus. max " is the mean C measured at steady-state conditions for a particular dose of everolimus in the absence of other drugs. max In some embodiments, the average C max The (%CV) measured after administration of everolimus 10 mg was 59.7 ± 16.9 (21.7%).

[0164]

[0173] In various other embodiments, the present disclosure provides a method for treating rheumatoid arthritis after discontinuing posaconazole treatment. The present invention discloses a method for treating a patient who is previously taking posaconazole by reducing the dose (e.g., about 10% to 50% of the reference dose) of a CYP3A4 substrate drug that is prohibited for use in combination with a strong CYP3A4 inhibitor for at least about 2 days to at least about 42 days, and the CYP3A4 substrate drug is a CYP3A4 inhibitor. max The usual baseline C max approximately 4000% or less of the normal baseline C maxabout 3950% or less, about 3900% or less, about 3850% or less, about 3800% or less, about 3750% or less, about 3700% or less, about 3650% or less, about 3600% or less, about 3550% or less, about 35 00% or less, approximately 3450% or less, approximately 3400% or less, approximately 3350% or less, approximately 3300% or less, approximately 3250% or less, approximately 3200% or less, approximately 3150% or less, approximately 3100% or less, approximately 3050% or less Lower, about 3000% or less, about 2950 or less, about 2900% or less, about 2850% or less, about 2800% or less, about 2750% or less, about 2700% or less, about 2650% or less, about 2600% or less, about 25 50% or less, approximately 2500% or less, approximately 2450% or less, approximately 2400% or less, approximately 2350% or less, approximately 2300% or less, approximately 2250% or less, approximately 2200% or less, approximately 2150% or less, approximately 2100% or less , about 2050% or less, about 2000% or less, about 1950% or less, about 1900% or less, about 1850% or less, about 1800% or less, about 1750% or less, about 1700% or less, about 1650% or less, about 16 00% or less, approximately 1550% or less, approximately 1500% or less, approximately 1450% or less, approximately 1400% or less, approximately 1350% or less, approximately 1300% or less, approximately 1250% or less, approximately 1200% or less, approximately 1150% or less , about 1100% or less, about 1050% or less, about 1000% or less, about 950% or less, about 900% or less, about 850% or less, about 800% or less, about 750% or less, about 700% or less, about 650% or less, about 600% or less, approximately 550% or less, approximately 500% or less, approximately 450% or less, approximately 445% or less, approximately 440% or less, approximately 435% or less, 430% or less, approximately 425% or less, approximately 420% or less, approximately 415% or less, Approx. 410% or less, approx. 405% or less, approx. 400% or less, approx. 395% or less, approx. 390% or less, approx. 385% or less, approx. 380% or less, approx. 375% or less, approx. % or less, approx. 325% or less, approx. 320% or less, approx. 315% or less, approx. 310% or less, approx. 305% or less, approx. 300% or less, approx. 295% or less, approx. 290% or less, approx. 285% or less, approx. In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the C of ranolazine is maintained at about 245% or less, about 240% or less, about 235% or less, 230% or less, about 225% or less, about 220% or less, about 215% or less, about 210% or less, 205% or less, about 200% or less, about 195% or less, about 190% or less, about 185% or less, about 180% or less, about 175% or less, about 170% or less, about 165% or less, about 160% or less, about 155% or less, about 150% or less, about 145% or less, about 140% or less, about 135% or less, 130% or less, about 125% or less, about 120% or less, about 115% or less, about 110% or less, about 105% or less, or about 100% or less (including all ranges and subranges). max is the normal baseline C max In another specific embodiment, the CYP3A4 substrate drug is lurasidone, and the C max is the normal baseline C max In another specific embodiment, the CYP3A4 substrate drug is tadalafil, and the C max is the normal baseline C max In another specific embodiment, the CYP3A4 substrate drug is erlotinib, and the C max is the usual baseline C max In another specific embodiment, the CYP3A4 substrate drug is solifenacin succinate, and the Cmax is the normal baseline C max In another specific embodiment, the CYP3A4 substrate drug is everolimus, and the C max is the normal baseline C max Maintain a level of approximately 200% or less.

[0165]

[0174] CYP3A4 substrate drugs (such as lurasidone and ranolazine) Therefore, traditionally, a CYP3A4 substrate drug should be administered one day after the last dose of posaconazole (i.e., one day after discontinuing or "stopping" posaconazole). It would be expected that interactions between posaconazole and many CYP3A4 substrate drugs would be safe. However, the interactions between posaconazole and many CYP3A4 substrate drugs have not been previously investigated. Applicant's clinical study is the first to observe the levels of a specific CYP3A4 substrate drug during concomitant administration of posaconazole and for an extended period of time after posaconazole administration has been discontinued. Applicant found that the inhibitory effect of posaconazole on CYP3A4 persists substantially longer than would be predicted from its half-life, and thus posaconazole inhibits the metabolism of CYP3A4 substrate drugs for a substantially longer period than would be predicted by the prior art. Therefore, the actual plasma concentration of the CYP3A4 substrate drug is actually significantly higher after discontinuing posaconazole than would be predicted by the prior art. Thus, to achieve a "safe" plasma concentration profile of a CYP3A4 substrate drug (e.g., where the benefits of treating a patient for a condition or disease for which the CYP3A4 substrate drug is indicated outweigh the risks associated with the effects of drug-drug interactions as described herein), Applicant has found that patients may have to wait longer than previously thought (e.g., longer than the one-day contraindication period provided on the label) and / or may have to be administered a reduced dose of the CYP3A4 substrate drug.

[0166]

[0175] For purposes of this method, a potent C agonist such as posaconazole or ketoconazole is used. The predicted plasma levels of a CYP3A4 substrate drug after discontinuation of coadministration with a strong CYP3A4 inhibitor can be determined using conventional pharmacological methods, such as: The plasma level of a CYP3A4 substrate drug can be calculated from the plasma level of the CYP3A4 substrate drug. Plasma levels can be described in various ways, such as area under the plasma concentration curve (AUC) and peak plasma concentration (Cmax). Baseline levels of a CYP3A4 substrate drug and posaconazole interaction levels can be compared using the geometric mean ratio (GMR) of AUC and Cmax. As used herein, "baseline" refers to the plasma concentration of a CYP3A4 substrate drug in an otherwise identical patient population not receiving a CYP3A4 inhibitor. GMR is a standard industry and regulatory method for assessing the ratio of change in a pharmacokinetic variable (such as AUC) to its own baseline value (e.g., in patients not treated with posaconazole). Knowing the level (AUC or Cmax) of the substrate drug during co-administration of posaconazole with a CYP3A4 substrate drug, a function can be derived using conventional pharmacological methods to estimate how the AUC or plasma level of the CYP3A4 substrate drug is expected to decay over time after posaconazole administration is discontinued. Such a function can be used to provide a plot of the decay GMR of AUC (or Cmax) of a CYP3A4 substrate drug due to its interaction with posaconazole versus time, based on the reported half-life of posaconazole. As the GMR curve approaches the time at which essentially all posaconazole would be predicted to have been eliminated by the known half-life of posaconazole, the GMR approaches a value of 1.

[0167]

[0176] Those skilled in the art will appreciate that the expected DDI decay curve can be calculated using Equation 1. (Rang, H., Dale, M., Ritter, J. and Flower R., Rang and Dale's Pharmacology, 6th ed. London:Elsevier, Ltd 2007. Chapter 8, p.122): AUC GMR on day (x) = 1 + [(AUC during co-administration)-1] * e^(-K el *x)(Formula 1) In the formula, K el = ln(2) / (31 hours / 24 hours) or approximately 0.5366 (the 31-hour half-life of a posaconazole tablet (Noxafil® label updated September 2016)) Based on, and where x = number of days after discontinuation of posaconazole.

[0168]

[0177] The predicted DDI decay curve is calculated by dividing the AUC during co-administration in Equation 1 by the C during co-administration. The AUC or Cmax GMR can also be calculated by substituting . As used herein, "predicted level" and "predicted level" and the like refer to the AUC or Cmax GMR value calculated using Equation 1.

[0169]

[0178] Applying Equation 1 to the AUC levels measured during co-administration with posaconazole This generated predicted DDI curves for lurasidone (Figure 8; solid line) and ranolazine (Figure 9; solid line). Clinically established co-administration levels for encorafenib (BRAFTOVI®) in the presence of posaconazole have also been determined. As shown in Table A, when co-administered with posaconazole, the baseline AUC of encorafenib increases by 300% due to a drug-drug interaction with posaconazole (see column titled "AUC Co-administration Level" "Percent of Baseline"). Equation 1 was applied to the co-administration AUC levels of encorafenib, and the predicted curves for the effect of posaconazole on the AUC of encorafenib GMR were calculated, as shown in Figure 10.

[0170]

[0179] Applicant surprisingly and unexpectedly found that after discontinuing posaconazole were found to have significantly elevated plasma levels of CYP3A4 substrate drugs administered to patients receiving posaconazole compared to the expected levels of such drugs, calculated using Equation 1. Accordingly, Applicant has demonstrated that the inhibitory effect of posaconazole on CYP3A4 substrate drugs persists much longer than previously known, and that administering a full base-line dose of CYP3A4 substrate drug after discontinuing posaconazole (e.g., as taught on the labeling of the CYP3A4 substrate drug described herein) actually achieves plasma levels of the CYP3A4 substrate drug that are higher than the expected levels, calculated, for example, using Equation 1 (see Figures 8 and 9; (dashed line). To address the clinical impact of this unexpected increase in plasma levels, Applicant has found that either (i) the full base dose of the CYP3A4 substrate drug should be administered for two or more days (e.g., as described herein) after discontinuing posaconazole to achieve safe plasma levels higher than predicted, or (ii) the dose of the CYP3A4 substrate drug should be reduced to achieve safe plasma levels of the drug approximately equivalent (e.g., about 80-125%) to the levels predicted from the full base dose of the CYP3A4 substrate drug based on, for example, the above equation. The reduced dose of the CYP3A4 substrate drug can be administered with posaconazole the day after discontinuing posaconazole or two or more days (e.g., as described herein) after discontinuing posaconazole.

[0171]

[0180] In some embodiments (e.g., more than 2 days after discontinuing posaconazole) When the full dose is subsequently administered, or when a reduced dose is administered as described herein, the plasma level of the CYP3A4 substrate drug will be at or below a target level considered therapeutic and safe (i.e., where inhibition of CYP3A4 by posaconazole will not pose an unacceptable risk of serious side effects to the patient). In Figure 10, a line is superimposed on the diagram showing the target AUC GMR level of encorafenib considered safe according to some embodiments. The present disclosure provides methods of administering encorafenib to achieve plasma levels higher than expected but not exceeding the target safe level. Thus, in various embodiments, the methods include (i) detecting plasma levels above levels predicted from a prediction curve (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, or about 195% above the predicted plasma level curve). or (ii) administering a reduced dose to achieve plasma levels equal to or greater than the level calculated for the full reference dose but not exceeding the target safety level.

[0172]

[0181] Lurasidone, ranolazine, and encorafenib are also effective against other CYP3 The predicted DDI decay curve for the plasma level of a CYP3A4 substrate drug can be calculated from the plasma levels of the CYP3A4 substrate drug obtained during co-administration with posaconazole and the conventionally understood half-life of posaconazole, for example, using Equation 1. Table A below contains (a) the co-administration levels of the CYP3A4 substrate drug in columns titled "AUC Co-administration Level" and "Cmax Co-administration Level"; (b) the "AUC Target Safe Level" and "Cmax Target Safe Level" (levels where the benefits outweigh the risks, according to some embodiments); and (c) the "Baseline AUC" and "Baseline Cmax" levels of the CYP3A4 substrate drug measured in patients not previously treated with a strong CYP3A4 inhibitor (e.g., posaconazole). The column titled "Co-administration Level" provides the fold change or percent of baseline increase observed when the substrate drug was co-administered with a strong CYP3A4 inhibitor (e.g., ketoconazole). Because coadministration of many of these CYP3A4 substrate drugs with strong CYP3A4 inhibitors is contraindicated, coadministration levels represent unsafe Cmax and AUC levels. In various embodiments, the "target safe level" is a non-limiting example of an upper limit of fold change or percent of baseline where, in some embodiments, the benefit of treating a patient for a condition or disease for which the CYP3A4 substrate drug is indicated outweighs the risks associated with drug-drug interaction effects. Table A provides an example of a target safe level for each CYP3A4 substrate drug. Although each drug may have multiple target safety levels (e.g., depending on specific risk / benefit considerations for different patient populations), "baseline AUC" or "baseline Cmax" refers to the plasma concentration of a CYP3A4 substrate drug in the same patient, except that they are not receiving a strong CYP3A4 inhibitor. The co-administration levels reported in Table A were measured with either posaconazole, itraconazole, ritonavir, or ketoconazole. For purposes of this method, plasma levels measured during co-administration of a CYP3A4 substrate drug with ketoconazole can be used to estimate the posaconazole DDI decay curve, e.g., using Equation 1. In some embodiments, the present disclosure provides methods of administering a CYP3A4 substrate drug to achieve plasma levels that are at or below the target safe AUC and Cmax shown in Table A. The plasma level of the CYP3A4 substrate drug can be measured using routine methods known in the art (e.g., obtaining a blood sample from the patient and measuring the plasma concentration of the CYP3A4 substrate drug using mass spectrometry) to determine when the plasma level is within a safe and effective level so that an appropriate delay period and / or reduced dose administration period can be calculated. The following section discusses how Applicant's surprising and unexpected information regarding CYP3A4 inhibition by posaconazole gleaned from Applicant's clinical studies informs the administration of CYP3A4 substrate drugs.

[0173] [Table 1]

[0174] [Table 2]

[0175] [Table 3]

[0176] [Table 4]

[0177] [Table 5]

[0178] [Table 6]

[0179] [Table 7]

[0180]

[0182] The values ​​in Table A are approximate. In some embodiments, the AUC and Cmax values ​​are The percent baseline of the target safety level can vary by about ±25% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, including all ranges therebetween). For example, if the target safety level in Table A is 130%, the AUC or Cmax level achieved can be 155% or 105%. Similarly, in some embodiments, the GMR of AUC or Cmax can vary by about +25%.

[0181]

[0183] Potentially harmful consequences of leaving patients untreated with CYP3A4 substrate drugs Because the potential risks associated with the effects of a DDI between a CYP3A4 substrate drug and posaconazole (e.g., elevated plasma levels and increased exposure to the CYP3A4 substrate drug) must be balanced against the potential risks, a skilled artisan (e.g., a physician) would administer a dose of the CYP3A4 substrate drug as soon as it is safe to do so. For example, a physician would administer the CYP3A4 substrate drug as soon as there is no clinically significant elevation in plasma levels or exposure to the CYP3A4 drug above a target level deemed safe. Even though lower posaconazole plasma levels would reduce the potential adverse effects of a DDI, such a physician would not wait a longer period because the patient would not benefit from treatment with the CYP3A4 substrate drug (or would be exposed to the risks associated with remaining untreated). For certain CYP3A4 substrate drugs, the CYP3A4 substrate drug is contraindicated for coadministration with posaconazole. Thus, one skilled in the art would interpret such a contraindication to mean that only co-administration of a CYP3A4 substrate drug with a CYP3A4 inhibitor (e.g., posaconazole) is unsafe, but that it is safe to administer 100% of the reference dose (as defined herein) of the CYP3A4 substrate drug immediately following the last dose of posaconazole (i.e., the day following "discontinuation" of posaconazole).

[0182]

[0184] However, applicants have not yet determined the inhibitory effect of posaconazole on CYP3A4. Applicants have found that posaconazole levels persist substantially longer than would be predicted from its half-life. Applicants have also found that posaconazole levels remain higher than expected for extended periods of time in obese patients, as defined herein. See Figure 8, which shows that the actual lurasidone AUC levels (dashed line) measured in patients after discontinuing posaconazole are unexpectedly higher than the levels (solid line) predicted by the prior art from the posaconazole half-life after discontinuing posaconazole. See also Figure 9, which shows that the actual ranolazine AUC levels (dashed line) are significantly higher than the predicted AUC levels (solid line). The previously unknown persistence of posaconazole inhibition of CYP3A4 poses a previously unrecognized increased risk of serious side effects with subsequent administration of CYP3A4 substrate drugs. To mitigate this risk, in some embodiments, administration of a CYP3A4 substrate drug is contraindicated not only for coadministration with posaconazole, but also for a period of time (e.g., two or more days) after discontinuing posaconazole beyond the one-day delay indicated on the label (i.e., contraindication to coadministration of a CYP3A4 substrate drug with posaconazole). In some embodiments, the methods provide for administering a CYP3A4 substrate drug as soon as it is safe to do so, for example, for a period of more than about one day, as described herein. Administering a CYP3A4 substrate drug "as soon as it is safe" does not mean waiting until all or nearly all of the posaconazole has been cleared from the patient to minimize DDIs. Rather, administering a CYP3A4 substrate drug "as soon as it is safe" generally means administering the CYP3A4 substrate drug even if the plasma levels of posaconazole are such that a significant DDI effect is still present. The CYP3A4 substrate drug is administered as soon as the effect of the DDI is sufficiently low so that the plasma level of the CYP3A4 substrate drug does not exceed the target safe level. This explains the need to treat patients with the CYP3A4 substrate drug without any unnecessary delay (after discontinuation of posaconazole) to minimize as much as possible the risk of leaving such patients untreated.

[0183]

[0185] As used herein, a CYP3A4 substrate drug is considered to be "as soon as it becomes safe" "Safe," as used herein, such as when administered at "safe levels," means as soon as inhibition of CYP3A4 by posaconazole no longer poses an unacceptable risk of serious side effects to the patient (e.g., due to plasma levels of the CYP3A4 substrate drug). An "unacceptable risk of serious side effects" occurs, for example, when the risks associated with increased exposure to the CYP3A4 substrate drug are, overall, greater than the risks of not treating the patient with the CYP3A4 substrate drug. In some embodiments, as unexpectedly discovered by applicants, administering a CYP3A4 substrate drug "as soon as safe" requires waiting longer than predicted by the prior art (i.e., waiting more than one day after discontinuing posaconazole based on a label-labeled contraindication for coadministration of a CYP3A4 substrate drug with posaconazole). By implication, "unsafe," as used herein, means when the risks associated with treating the patient (e.g., high exposure to the CYP3A4 substrate drug) are greater than the risks of not treating the patient. Thus, the present method accounts for the previously unknown magnitude and unknown duration of the inhibitory effect of posaconazole on CYP3A4 and the need to treat patients with CYP3A4 substrate drugs.

[0184]

[0186] In some embodiments, treatment provides a favorable risk / benefit profile A CYP3A4 substrate drug is then administered. The risk / benefit profile weighs the patient's risk of potential adverse events from treatment compared with the benefits of treatment. Non-limiting examples of factors used to evaluate the risk / benefit profile include: (i) the type of benefit the patient will receive (e.g., the treatment endpoint and the value of the treatment to the patient); (ii) the magnitude of the benefit; (iii) the likelihood that the patient will experience one or more benefits; (iv) the duration of the effect, and whether the duration will be a benefit; (v) the severity, type, number, and rate of adverse events (e.g., serious adverse events and non-serious adverse events); (vi) the likelihood of the adverse event (e.g., the percentage of the patient population expected to experience the adverse event; the incidence of each adverse event in the study population; the degree of uncertainty in the probability of the decision; the patient's willingness to accept the assumed risk of the adverse event given the assumed benefit); (vii) the duration of the adverse event (e.g., how long the adverse event lasts and whether it is reversible; the type of intervention needed to address the adverse event); and (viii) medical need (e.g., whether the CYP3A4 substrate drug provides a benefit or addresses a need not met by other therapies). In the context of potential drug-drug interactions between CYP3A4 inhibitors, such as posaconazole, and CYP3A4 substrate drugs (including those disclosed herein), appropriate administration of a CYP3A4 substrate drug in the presence of a CYP3A4 inhibitor requires balancing various risk and benefit factors (e.g., as described above). Appropriate dosages for CYP3A4 substrate drugs resulting from an evaluation of the risk / benefit profile are routinely incorporated into FDA-approved drug labels. To be clear, PK elevation (e.g., Cmax, AUC, or GMR of AUC or Cmax) is not the only factor that a person skilled in the art (e.g., a physician) would consider relevant when deciding whether to administer a CYP3A4 substrate drug. In some embodiments, a patient is administered a CYP3A4 substrate drug as soon as the benefits outweigh the risks. In some embodiments, a patient is administered a full standard dose as soon as the benefits outweigh the risks. In some embodiments, a patient is administered a reduced dose as soon as the benefits outweigh the risks.

[0185]

[0187] In some embodiments, the CYP3A4 substrate drug is a CYP3A4 substrate drug The CYP3A4 substrate drug is administered as soon as at least one of the Cmax, AUC, and GMR of AUC or Cmax is at a safe level after such administration. In some embodiments, the safe level is lower than the co-administration level of Cmax, AUC, and / or GMR shown in Table A for the CYP3A4 substrate drug, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 50%, or about 60% lower than the co-administration level. 5%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% lower. In some embodiments, the CYP3A4 substrate drug is administered as soon as at least one or more of the Cmax, AUC, mean AUC, and GMR of AUC or Cmax of the CYP3A4 substrate drug increase to an unexpected level (e.g., higher than an expected level) (a level that would be considered likely to occur based on an understanding of the impact of conventional CYP3A4 inhibitors (e.g., posaconazole) on such levels of the CYP3A4 substrate drug). In some embodiments, the CYP3A4 substrate drug is administered in a manner that, after discontinuation of posaconazole, the Cmax or AUC of the CYP3A4 substrate drug is about 3000%, about 2900%, about 2800%, about 2700%, about 2600%, about 2500%, about 2400%, about 2300%, about 2200%, about 2100% of the normal baseline value for each of such parameters (Table A). ,approximately 2000%,approximately 1900%,approximately 1800%,approximately 1700%,approximately 1600%,approximately 1500%,approximately 1400%,approximately 1300%,approximately 1200%,approximately 1100%,approximately 1000%,approximately 990%,approximately 980%,approximately 970%,approximately 960%,approximately 950%,approximately 940%,approximately 930%,approximately 920%,approximately 910%,approximately 900%,approximately 590%,approximately 580%,approximately 570%,approximately 560 %, approx. 550%, approx. 540%, approx. 530%, approx. 520%, approx. 510%, approx. 500%, approx. 490%, approx. 480%, approx. 470%, approx. 460%, approx. 450%, approx. 440%, approx. 430%, approx. 420%, approx. 410%, approx. 400%, approx. 390%, approx. 380%, approx. 370%, approx. 360%, approx. 350%, approx. 340%, approx. 330%, approx. 320%, approx. 310%, approx. 300%, approx. It may be safely administered as soon as the dose reaches 290%, about 280%, about 270%, about 260%, about 250%, about 240%, about 230%, about 220%, about 210%, about 200%, about 190%, about 180%, about 170%, about 160%, about 150%, about 140%, about 130%, about 120%, about 110%, and about 105%, inclusive of all ranges and subranges thereof.In some embodiments, the CYP3A4 substrate drug can be safely administered as soon as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days (including all values ​​and ranges therebetween) after discontinuation of posaconazole. In some embodiments, after discontinuation of posaconazole, the GMR of AUC or Cmax of the CYP3A4 substrate drug is increased by about 30-fold, about 29-fold, about 28-fold, about 27-fold, about 26-fold, about 25-fold, about 24-fold, about 23-fold, about 22-fold, about 21-fold, about 20-fold, about 19-fold, about 18-fold, about 17-fold, about 16-fold, about 15-fold, about 14-fold, about 13-fold, about 12-fold, about 11-fold, about 10-fold, about 9.9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 14-fold, about 15-fold, about 16-fold, about 16-fold, about 17-fold, about 17-fold, about 18-fold, about 18-fold, about 19-fold, about 19-fold, about 20-fold, about 20-fold, about 21-fold, about 22-fold, about 23-fold, about 24-fold, about 25-fold, about 26-fold, about 27-fold, about 28-fold, about 29-fold, about 30-fold, about 31-fold, about 32-fold, about 33-fold, about 34-fold, about 35-fold, about 36-fold, about 37-fold, about 38-fold, about 39-fold, about 40-fold, about 41-fold, about 42-fold, about 43-fold, about 44-fold, about 45-fold, about 46-fold, about 47-fold, about 48-fold, about 49 9.8 times, approximately 9.7 times, approximately 9.6 times, approximately 9.5 times, approximately 9.4 times, approximately 9.3 times, approximately 9.2 times, approximately 9.1 times, approximately 9 times, approximately 8.9 times, approximately 8.8 times, approximately 8.7 times, approximately 8.6 times, approximately 8.5 times, approximately 8.4 times, approximately 8.3 times, approximately 8.2 8.1 times, 8.0 times, 7.9 times, 7.8 times, 7.7 times, 7.6 times, 7.5 times, 7.4 times, 7.3 times, 7.2 times, 7.1 times, 7.0 times, 6.9 times, 6.8 times, 6.7 times, 6.6 times , approximately 6.5 times, approximately 6.4 times, approximately 6.3 times, approximately 6.2 times, approximately 6.1 times, approximately 6.0 times, approximately 5.9 times, approximately 5.8 times, approximately 5.7 times, approximately 5.6 times, approximately 5.5 times, approximately 5.4 times, approximately 5.3 times, approximately 5.2 times, approximately 5.1 times, approximately 5.0 times, Approximately 4.9 times, approximately 4.8 times, approximately 4.7 times, approximately 4.6 times, approximately 4.5 times, approximately 4.4 times, approximately 4.3 times, approximately 4.2 times, approximately 4.1 times, approximately 4.0 times, approximately 3.9 times, approximately 3.8 times, approximately 3.7 times, approximately 3.6 times, approximately 3.5 times, approximately 3.4 times, approximately As soon as the CYP3A4 substrate drug concentration is 3.3-fold, about 3.2-fold, about 3.1-fold, about 3.0-fold, about 2.9-fold, about 2.8-fold, about 2.7-fold, about 2.6-fold, about 2.5-fold, about 2.4-fold, about 2.3-fold, about 2.2-fold, about 2.1-fold, about 2.0-fold, about 1.9-fold, about 1.8-fold, about 1.7-fold, about 1.6-fold, about 1.5-fold, about 1.4-fold, about 1.3-fold, about 1.2-fold, about 1.1-fold, and about 1.05-fold (including all ranges therebetween), the CYP3A4 substrate drug can be safely administered.In some embodiments, the CYP3A4 substrate drug is administered at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 It can be safely administered as soon as 6, 37, 38, 39, 40, 41, or 42 days after discontinuation of posaconazole (including all values ​​and ranges therebetween). In some embodiments, the patient is administered a full standard dose of the CYP3A4 substrate drug to achieve any of the above Cmax or AUC values ​​or any of the above fold-changes in GMR of Cmax or AUC. In some embodiments, after discontinuation of posaconazole, the patient is administered a reduced dose of the CYP3A4 substrate drug to achieve any of the above Cmax or AUC values ​​or any of the above fold-changes in GMR of Cmax or AUC.

[0186]

[0188] In some embodiments, the methods disclosed herein are based on conventionally understood The present invention provides for administering a dose of a CYP3A4 substrate to achieve one or more PK parameters (AUC, Cmax, and GMR of AUC or Cmax) that exceed the respective values ​​predicted for that dose of the CYP3A4 substrate drug based on the posaconazole half-lives of 27 hours (patients with normal hepatic function), 39 hours (patients with mild hepatic impairment), 27 hours (patients with moderate hepatic impairment), and 43 hours (patients with severe hepatic impairment), approximately 24 hours after administration of posaconazole injection, approximately 31 hours after administration of posaconazole delayed-release tablets, and approximately 31 to 37 hours after administration of posaconazole oral suspension. Noxafil® label, revised September 2016. Figure 8 shows the predicted half-life of posaconazole listed on the Noxafil® label using Equation 1 and a posaconazole half-life of 31 hours. Figure 1 shows the actual lurasidone AUC levels (as a multiple of baseline AUC; dashed line) resulting from administration of 100% of the reference dose in normal weight and obese patients at various time points after discontinuing posaconazole measured in Applicant's studies compared to predicted lurasidone levels ("predicted levels; actual"). The solid lines show that predicted lurasidone AUC levels (reported as GMR) are approximately 400% (or approximately 4-fold) greater than baseline 1 day after discontinuing posaconazole, approximately 300% (or approximately 3-fold) greater than baseline 2 days after discontinuing posaconazole, and approximately 200% (or approximately 2-fold) greater than baseline 3 days after discontinuing posaconazole, then gradually decrease until they reach baseline around day 9 after discontinuing posaconazole. In contrast, Applicant's data show that actual lurasidone AUC levels are significantly above predicted levels for at least 14 days after discontinuation of posaconazole, e.g., approximately 2-fold greater than predicted 2 days after discontinuation of posaconazole, approximately 2-3-fold greater than predicted 3 days after discontinuation of posaconazole, and approximately 2.5-3.5-fold greater than predicted 4 days after discontinuation of posaconazole, and remain approximately 2-3 times the predicted level for at least about 14 days. The same study was conducted with ranolazine. Similar to Figure 8, Figure 9 shows the lurasidone AUC levels predicted from the 31-hour posaconazole half-life listed on the Noxafil® label. 1 shows actual ranolazine AUC levels (as a fold of baseline AUC; dashed line) in normal weight and obese patients resulting from administration of 100% of the reference dose at various time points after discontinuation of posaconazole measured in Applicants' studies compared to ranolazine levels ("predicted levels"; solid lines). Applicants' data demonstrate that actual ranolazine AUC levels significantly exceed predicted levels for at least 14 days after discontinuation of posaconazole, e.g., about 0.5-1.5-fold greater than predicted 2 days after discontinuing posaconazole, about 1.5-fold greater than predicted 3 days after discontinuing posaconazole, about 1.5-fold greater than predicted 4 days after discontinuing posaconazole, and remain at about 0.5-1.5-fold the predicted level for at least about 14 days. In some embodiments, the method involves administering a CYP3A4 substrate drug (e.g., lurasidone, ranolazine, or any other CYP3A4 substrate drug such as those described herein) to achieve plasma levels that exceed the expected levels measured for a reference dose.

[0187]

[0189] In some embodiments, the method comprises administering lurasidone at an AU of 100 mg / kg, as shown in FIG. In some embodiments, lurasidone is administered on specific days after discontinuing posaconazole when at least one of the C, Cmax, and / or AUC or GMR of Cmax exceeds predicted levels (e.g., a DDI decay curve calculated using Equation 1 and the observed half-life of posaconazole). In some embodiments, lurasidone is administered on days ... AUC or Cmax of lurasidone exceeds predicted levels (e.g., a DDI decay curve calculated using Equation 1 and the observed half-life of posaconazole). at least one of the following is about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, about 210%, about 215%, about 216%, about 220%, about 225%, about 230%, about 235%, about 240%, about 245%, about 250%, about 255% of the baseline level; about 260%, about 265%, about 270%, about 275%, about 280%, about 285%, about 290%, about 295%, about 300%, about 305%, about 310%, about 315%, about 320%, about 325%, about 330%, about 335%, about 340%, about 345%, about 350%, about 355%, about 360%, about 365%, about 370%, about 375%, about 380%, about 385%, about 390%, about 395%, or about 400% (including all values ​​and ranges therebetween). In some embodiments, the lurasidone is administered in a dose-dependent manner such that at least one of the GMRs of AUC or Cmax of lurasidone is about 1.05-fold, about 1.1-fold, about 1.15-fold, about 1.2-fold, about 1.25-fold, about 1.3-fold, about 1.35-fold, about 1.4-fold, about 1.45-fold, about 1.50-fold, about 1.55-fold, about 1.6-fold, about 1.65-fold, about 1.7-fold, about 1.75-fold, about 1.8-fold, about 1.85-fold, about 1.90-fold, about 1.95-fold, about 2.0-fold, about 2.1-fold, about 2.15-fold, about 2.16-fold, about 2.2-fold, about 2.24-fold, about 2.25-fold, about 2.3-fold, about 2.35-fold, about 2.4-fold, about 2.45-fold, about 2.50-fold, about 2.55-fold, about 2.60-fold, about 2.70-fold, about 2.75-fold, about 2.80-fold, about 2.85-fold, about 2.90-fold, about 2.95-fold, about 3.00-fold, about 3.01-fold, about 3.02-fold, about 3.03-fold, about 3.04-fold, about 3.05-fold, about 3.06-fold, about 3.07-fold, about 3.08-fold, about 3.09-fold, about 3.10-fold, about 3.11-fold, about 3.12-fold, about 3.13-fold, about 3.14- fold, about 2.50-fold, about 2.55-fold, about 2.60-fold, about 2.65-fold, about 2.7-fold, about 2.75-fold, about 2.8-fold, about 2.85-fold, about 2.9-fold, about 2.95-fold, about 3.0-fold, about 3.05-fold, about 3.1-fold, about 3.15-fold, about 3.20-fold, about 3.25-fold, about 3.30-fold, about 3.35-fold, about 3.40-fold, about 3.45-fold, about 3.50-fold, about 3.55-fold, about 3.60-fold, about 3.65-fold, about 3.7-fold, about 3.75-fold, about 3.8-fold, about 3.85-fold, about 3.9-fold, about 3.95-fold, or about 4.0-fold (including all values ​​and ranges therebetween).In some embodiments, administration of lurasidone (e.g., 100% of the baseline dose or a reduced dose) is initiated immediately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days (including all values ​​and subranges therebetween) after discontinuation of posaconazole.

[0188]

[0190] In some embodiments, the method comprises administering the AU of ranolazine, as shown in FIG. The present invention provides for administering ranolazine on specific days after discontinuing posaconazole when at least one of the C, Cmax, and / or AUC or GMR of Cmax exceeds predicted levels (e.g., a DDI decay curve calculated using Equation 1 and the observed half-life of posaconazole). In some embodiments, ranolazine is administered when at least one of the AUC or Cmax of ranolazine is about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% of baseline levels (including all values ​​and ranges therebetween). In some embodiments, ranolazine is administered when at least one of the GMRs of AUC or Cmax of ranolazine is increased by about 1.05-fold, about 1.1-fold, about 1.15-fold, about 1.2-fold, about 1.25-fold, about 1.3-fold, about 1.35-fold, about 1.4-fold, about 1.45-fold, or about 1.50-fold. In some embodiments, administration of ranolazine (e.g., 100% of the base dose or a reduced dose) is initiated immediately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days (including all values ​​and subranges therebetween) after discontinuation of posaconazole.

[0189]

[0191] Observations from Applicant's clinical studies of lurasidone and ranolazine indicate that administration of other CYP3A4 substrate drugs should be discontinued at least 2 days (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 In some embodiments, Applicant has found that after discontinuation of posaconazole, the CYP3A4 substrate drug can be administered after one or more of the Cmax, AUC, and / or GMR of AUC or Cmax of the CYP3A4 substrate drug have risen to unexpected levels (e.g., a DDI decay curve calculated using Equation 1 and the observed half-life of posaconazole), and indeed on certain days that were thought to be highly unlikely after discontinuation of posaconazole treatment. Because certain plasma levels may be unsafe, in some embodiments, the methods of the present invention administer a CYP3A4 substrate drug when (e.g., as soon as) at least one of the AUC, Cmax, or GMR of AUC or Cmax of the CYP3A4 substrate drug is at or below a maximum level and greater than a predicted level. In some embodiments, the maximum level is the plasma level of the CYP3A4 substrate drug at which the benefits of treating the patient with the CYP3A4 substrate drug outweigh the risks. Above the maximum level, the risks of treatment outweigh the benefits. Non-limiting examples of maximum levels for various CYP3A4 substrate drugs are shown in Table A, "Target Safe Levels."Because certain plasma levels may not be safe, in some embodiments, if at least one of the actual AUC or Cmax of the CYP3A4 substrate drug is about 3000% to about 105% of the predicted AUC or Cmax, e.g., about 3000%, about 2900%, about 2800%, about 2700%, about 2600%, about 2500%, about 2400%, about 2300%, about 2200%, about 2100%, about 2000%, about 1900%, about 1800%, about 1700%, about 1600%, about 1500%, about 1400%, about 1300%, about 1200%, about 1400%, about 1500%, about 1600%, about 1700%, about 1800%, about 1900%, about 2100%, about 2200%, about 2300%, about 2400%, about 2500%, about 2600%, about 2700%, about 2800%, about 2900%, about 3000%, about 3100%, about 3200%, about 3300%, about 3400%, about 3500%, about 3600%, about 3700%, about 3800%, about 3900%, about 4000%, about 4100%, about 4200%, about 4300%, about 4400%, about 4500%, about 4600%, about 4700%, about 4800%, about 4900%, about 5000%, about 5100%, about 5200%, about 5300%, about 5400%, about 5500%, about 5600%, about 5700%, about 5800%, about 5900 %, about 1100%, about 1000%, about 950%, about 900%, about 850%, about 800%, about 750%, about 700%, about 650%, about 600%, about 550%, about 500%, about 450%, about 400%, about 350%, about 300%, about 250%, about 200%, about 190%, about 180%, about 170%, about 160%, about 150%, about 145%, about 140%, about 135%, about 130%, about 125%, about 120%, about 115%, about 110%, and about 105%, inclusive of all ranges and subranges, a CYP3A4 substrate drug is administered.In some embodiments, after discontinuation of posaconazole, at least one of the GMRs of AUC or Cmax is about 30-fold to about 1.05-fold of the baseline AUC or Cmax, e.g., about 30-fold, about 29-fold, about 28-fold, about 27-fold, about 26-fold, about 25-fold, about 24-fold, about 23-fold, about 22-fold, about 21-fold, about 20-fold, about 19-fold, about 18-fold, about 17-fold, about 16-fold, about 15-fold, about 14-fold, or about 18-fold, as compared to the normal baseline value of such parameter, respectively. , 13x, 12x, 11x, 10x, 9.9x, 9.8x, 9.7x, 9.6x, 9.5x, 9.4x, 9.3x, 9.2x, 9.1x, 9x, 8.9x, 8.8x, 8.7x, 8. 6 times, approximately 8.5 times, approximately 8.4 times, approximately 8.3 times, approximately 8.2 times, approximately 8.1 times, approximately 8.0 times, approximately 7.9 times, approximately 7.8 times, approximately 7.7 times, approximately 7.6 times, approximately 7.5 times, approximately 7.4 times, approximately 7.3 times, approximately 7.2 times, approximately 7.1 times, approximately 7.0 times, approximately 6.9 times, approximately 6.8 times, approximately 6.7 times, approximately 6.6 times, approximately 6.5 times, approximately 6.4 times, approximately 6.3 times, approximately 6.2 times, approximately 6.1 times, approximately 6.0 times, approximately 5.9 times, approximately 5.8 times, approximately 5.7 times, approximately 5.6 times, approximately 5.5 times, approximately 5.4 times, approximately 5.3 times , approximately 5.2 times, approximately 5.1 times, approximately 5.0 times, approximately 4.9 times, approximately 4.8 times, approximately 4.7 times, approximately 4.6 times, approximately 4.5 times, approximately 4.4 times, approximately 4.3 times, approximately 4.2 times, approximately 4.1 times, approximately 4.0 times, approximately 3.9 times, approximately 3.8 times, approximately 3.7 times, approximately 3. A CYP3A4 substrate drug is administered at about 6-fold, about 3.5-fold, about 3.4-fold, about 3.3-fold, about 3.2-fold, about 3.1-fold, about 3.0-fold, about 2.9-fold, about 2.8-fold, about 2.7-fold, about 2.6-fold, about 2.5-fold, about 2.4-fold, about 2.3-fold, about 2.2-fold, about 2.1-fold, about 2.0-fold, about 1.9-fold, about 1.8-fold, about 1.7-fold, about 1.6-fold, about 1.5-fold, about 1.4-fold, about 1.3-fold, about 1.2-fold, about 1.1-fold, and about 1.05-fold (including all ranges therebetween). In some embodiments, administration is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 days after discontinuation of posaconazole. , 41, or 42 days after discontinuation of posaconazole, including all values ​​and ranges therebetween. For example, in some embodiments, lurasidone is administered to achieve an AUC of about 400% to 105%, about 300% to about 105%, or about 216% to 105% of normal baseline, which can occur 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days after discontinuation of posaconazole. As another example, in some embodiments, ranolazine is administered to provide an AUC of about 150% to about 105% of normal baseline, which can occur 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days after discontinuation of posaconazole.

[0190]

[0192] In some embodiments, the methods of the present invention involve administering a CYP3A4 substrate drug. This requires that the substrate drug not be administered if, when administered, the plasma level of the substrate drug (i.e., at least one of AUC, Cmax, or GMR of AUC or Cmax) exceeds a certain maximum level (e.g., about 25%) that would otherwise occur. That is, in some embodiments, the maximum level determines when the CYP3A4 substrate drug is administered, and the CYP3A4 substrate drug is administered only if at least one of AUC, Cmax, or GMR of AUC or Cmax is at or below the maximum level. In some embodiments, the maximum level is less than at least one of AUC, Cmax, or GMR of AUC or Cmax of the CYP3A4 substrate drug that occurs when the substrate drug is co-administered with posaconazole (see AUC and Cmax co-administration levels in Table A). In some embodiments, the maximum level is the plasma level at which the benefits of treating the patient with the CYP3A4 substrate drug outweigh the risks. In some embodiments, the maximum level is the target safety level provided in Table A. If administration of a CYP3A4 substrate drug causes at least one of the AUC, Cmax, or GMR levels of AUC or Cmax to exceed the target safety level, administration is delayed until the AUC, Cmax, or at least one of the GMR levels of AUC or Cmax falls below the target safety level.

[0191]

[0193] In some embodiments, the maximum level is associated with the incidence of an adverse event. In some embodiments, the incidence of adverse events establishing a maximum level is at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% in a population of patients receiving the same treatment. In some embodiments, the decision to administer a CYP3A4 substrate drug is based on a risk / benefit analysis (e.g., as described above).

[0192]

[0194] Using lurasidone as an example, there was an approximately 300% increase in the AUC of lurasidone. An increase of approximately 3-fold in GMR is associated with somnolence, and an increase of 400% in AUC (or an increase of approximately 4-fold in GMR) is associated with akathisia. To benefit patients, in some embodiments, lurasidone is administered when AUC increases by up to approximately 300% (an increase of approximately 3-fold in GMR), but not when AUC increases by approximately 400% (an increase of approximately 4-fold in GMR). In some embodiments, the maximum level of lurasidone is a 216% increase in baseline AUC. In some embodiments, for example, if the patient's need for treatment outweighs the risks, the maximum level may be an increase of approximately 500% of baseline AUC. In other embodiments, the maximum level may be any value ranging from less than 500% to 216% of baseline AUC, including any range therebetween. Thus, in some embodiments, the maximum level of lurasidone is 400%, approximately 300%, or approximately 216% of the normal baseline level of AUC. Thus, in some embodiments, Lurasidone had an AUC of approximately 400%, approximately 350%, approximately 300%, approximately 275%, approximately 250%, approximately 225%, approximately 216%, approximately 215%, approximately 210%, approximately 205%, approximately 200%, approximately 195%, approximately 190%, approximately 185%, approximately 180%, approximately 175%, approximately 170%, approximately 165%, approximately 160%, approximately 155%, approximately 150%, approximately 145%, approximately 140%, approximately 135%, approximately 130%, and approximately 155%. It is administered as soon as the reduction in blood cholesterol level reaches 25%, about 120%, about 115%, about 110%, about 105% or less (including all values ​​and ranges therebetween), which may occur at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 days after discontinuation of posaconazole.

[0193]

[0195] In some embodiments, at least one of AUC or Cmax is greater than or equal to CYP3 A4 is when the AUC is greater than about 3000% of the normal baseline AUC (as defined above) of the substrate drug, e.g., greater than about 2900%, greater than about 2800%, greater than about 2700%, greater than about 2600%, greater than about 2500%, greater than about 2400%, greater than about 2300%, greater than about 2200%, greater than about 2100%, greater than about 2000%, greater than about 1900%, greater than about 1800%, greater than about 1700%, greater than about 1600%, greater than about 1500%, greater than about 1400%, greater than about 1300%, greater than about 1200%, greater than about 1100%, greater than about 1000%, greater than about 950%, greater than about 900%, greater than about 850%, If the CYP3A4 substrate is greater than 0%, greater than about 800%, greater than about 750%, greater than about 700%, greater than about 650%, greater than about 600%, greater than about 550%, greater than about 500%, greater than about 450%, greater than about 400%, greater than about 350%, greater than about 300%, greater than about 250%, greater than about 200%, greater than about 190%, greater than about 180%, greater than about 170%, greater than about 160%, greater than about 150%, greater than about 145%, greater than about 140%, greater than about 135%, greater than about 130%, greater than about 125%, greater than about 120%, greater than about 115%, or greater than about 110% (including all ranges and subranges thereof), then no CYP3A4 substrate drug is administered. In some embodiments, if at least one of the GMRs of AUC or Cmax is greater than about 30-fold the normal baseline AUC (as defined above) of the CYP3A4 substrate drug, e.g., greater than about 30-fold, greater than about 29-fold, greater than about 28-fold, greater than about 27-fold, greater than about 26-fold, greater than about 25-fold, greater than about 24-fold, greater than about 23-fold, greater than about 22-fold, greater than about 21-fold, greater than about 20-fold, greater than about 19-fold, greater than about 18-fold, greater than about 17-fold, greater than about 16-fold, greater than about 15-fold, greater than about 14-fold, greater than about 13-fold, greater than about 12-fold, greater than about 11-fold, greater than about 10-fold, greater than about 9-fold, or greater than about 10-fold. If the CYP3A4 substrate drug is greater than about 0.5-fold, greater than about 9.0-fold, greater than about 9.5-fold, greater than about 8.0-fold, greater than about 7.5-fold, greater than about 7.0-fold, greater than about 6.5-fold, greater than about 6.0-fold, greater than about 5.5-fold, greater than about 5.0-fold, greater than about 4.5-fold, greater than about 4.0-fold, greater than about 3.5-fold, greater than about 3.0-fold, greater than about 2.5-fold, greater than about 2.0-fold, greater than about 1.9-fold, greater than about 1.8-fold, greater than about 1.7-fold, greater than about 1.6-fold, greater than about 1.5-fold, greater than about 1.4-fold, greater than about 1.3-fold, greater than about 1.2-fold, or greater than about 1.1% (including all ranges and subranges thereof), then a CYP3A4 substrate drug will not be administered.

[0194]

[0196] As discussed herein, Applicant has identified posaconazolam for CYP3A4. We have found that the inhibitory effect of posaconazole persists substantially longer than would be predicted by its half-life. Thus, in some embodiments, the present methods provide for administering a CYP3A4 substrate drug as soon as sufficient posaconazole has been cleared from the patient so that a drug-drug interaction between posaconazole and the CYP3A4 substrate drug (e.g., a clinically relevant adverse event associated with elevated levels of the CYP3A4 substrate drug) does not pose an unacceptable risk to the patient. As described in Examples 2 and 3, the elimination half-life of posaconazole differs between normal-weight and obese patients; therefore, the delay period required to safely administer a CYP3A4 substrate drug after discontinuing posaconazole may differ in these patient populations. Specifically, Applicant has measured the elimination half-life of posaconazole in normal-weight patients to be 33.6 hours, while the elimination half-life of posaconazole in obese patients was measured to be 58.3 hours. Table B shows the mean steady-state concentrations of posaconazole measured for normal and obese patients in two separate clinical trials (BOW-001 and BOW-002) conducted by applicant. The same protocol was used to measure the elimination half-life of posaconazole in both clinical studies, which allowed for the combination of data from normal patients in each study ("All Normal") and obese patients in each study ("All Obese").

[0195] [Table 8]

[0196]

[0198] In some embodiments, the CYP3A4 substrate drug is at least one of posaconazole. The compound is administered after at least about two half-lives, e.g., about 2 half-lives, about 3 half-lives, about 4 half-lives, about 5 half-lives, about 6 half-lives, about 7 half-lives, about 8 half-lives, about 9 half-lives, about 10 half-lives, about 11 half-lives, about 12 half-lives, about 13 half-lives, about 14 half-lives, about 15 half-lives, about 16 half-lives, about 17 half-lives, about 18 half-lives, about 19 half-lives, about 20 half-lives, about 21 half-lives, about 22 half-lives, about 23 half-lives, about 24 half-lives, about 25 half-lives, about 26 half-lives, about 27 half-lives, about 28 half-lives, about 29 half-lives, or about 30 half-lives, or more (including all values ​​and subranges therebetween).

[0197]

[0199] In some embodiments, the timing of administration of a CYP3A4 substrate drug is In some embodiments, the CYP3A4 substrate drug is administered when the posaconazole level is reduced by at least about 50% of the steady-state level, e.g., about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 87.5%, about 90%, about 93.75%, about 95%, about 96.875%, about 98.4375%, or about 99%, including all values ​​and subranges therebetween. In some embodiments, the CYP3A4 substrate drug is administered as soon as posaconazole levels reach about 50% of steady-state levels, e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 12.5%, about 10%, about 6.25%, about 5%, about 3.125%, about 1.5625%, or about 1% of steady-state levels (including all values ​​and subranges therebetween).

[0198]

[0200] In some embodiments, the CYP3A4 substrate drug satisfies the following two conditions: The CYP3A4 substrate drug is administered immediately after the administration of the CYP3A4 substrate drug. (i) The posaconazole level is reduced by at least about 50% of the steady-state level, e.g., by about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 87.5%, about 90%, about 93.75%, about 95%, about 96.875%, about 98.4375%, or about 99%, including all values ​​and subranges therebetween; and (ii) the plasma level of the CYP3A4 substrate drug is at or below a target level considered safe but above an expected level of the CYP3A4 substrate drug. The expected level of the CYP3A4 substrate drug can be calculated using Equation 1. In some embodiments, the target level considered safe is the "target safe level" disclosed in Table A for the CYP3A4 substrate drug.

[0199]

[0201] In some embodiments, the method comprises administering to a subject a CYP3A4 substrate drug (as defined herein). The present invention provides for administering a reduced dose (as defined above, relative to a baseline dose) to a patient. The reduced dose can be administered simultaneously with posaconazole, the day after discontinuing posaconazole, or after any delay period described herein (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days after discontinuing posaconazole). In some embodiments, the reduced dose is administered for about 7 days to about 42 days, e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 days (including all values ​​and subranges therebetween). In some embodiments, the method provides for selecting a reduced reference dose that results in a maximum AUC in the range of about 500% to about 100% of the normal baseline AUC of the reference dose (e.g., about 500%, about 475%, about 450%, about 425%, about 400%, about 375%, about 350%, about 325%, about 300%, about 275%, about 250%, about 225%, about 200%, about 175%, about 150%, about 125%, and about 100%, including all values ​​and subranges therebetween), and then administering the reference dose to the patient on a day when the reduced reference dose provides an AUC that is less than 100% of the normal baseline. In some embodiments, the patient is administered the reference dose before a day when the reduced dose provides an AUC that is less than 100% of the normal baseline, provided that the AUC does not exceed safety levels as described herein when the reference dose is administered. In some embodiments, the AUC, Cmax, GMR AUC, or GMR Cmax provided by administering the reduced dose of the CYP3A4 substrate drug is between the baseline value and the target safety value listed in Table A for the CYP3A4 substrate drug.

[0200]

[0202] For example, in some embodiments, the methods of the present disclosure may include measuring the patient's normal baseline The method provides for administering a reduced dose of lurasidone that provides a maximum GMR of about 4.34 to 1 in a patient's daily dose, and then administering the reference dose to the patient on a day when the reduced reference dose provides a GMR of 1 or less. In some embodiments, the reference dose of lurasidone can be about 120 mg. In some embodiments, the patient discontinues taking lurasidone while being treated with posaconazole; the patient then discontinues treatment with posaconazole and begins administering a reduced dose of lurasidone (e.g., about 60 to 80 mg) for about 21 to 28 days anywhere from 1 to 3 days after discontinuing posaconazole; and on a day ranging from about 21 to 28 days after discontinuing posaconazole, the patient begins administering the 120 mg reference dose of lurasidone. Alternatively, in some embodiments, patients may receive 60 mg of lurasidone from about 9 to about 12 days after discontinuing posaconazole, and then the patient begins receiving the standard dose of 120 mg.

[0201]

[0203] In some embodiments, the reduced dose of the CYP3A4 substrate drug is posako. The dose is administered as soon as the nazole level reaches about 50% of the steady-state level, e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 12.5%, about 10%, about 6.25%, about 5%, about 3.125%, about 1.5625%, or about 1% of the steady-state level (including all values ​​and subranges therebetween).

[0202]

[0204] In some embodiments, the reduced dose of a CYP3A4 substrate drug is one of the following two: The drug is administered as soon as two conditions are met: (i) posaconazole levels are reduced by at least about 50% of steady-state levels, e.g., by about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 87.5%, about 90%, about 93.75%, about 95%, about 96.875%, about 98.4375%, or about 99% (including all values ​​and subranges therebetween); and (ii) plasma levels of the CYP3A4 substrate drug are reduced to levels considered safe. The target level is below the target level expected for the CYP3A4 substrate drug, but above the expected level for the CYP3A4 substrate drug. The expected level for the CYP3A4 substrate drug can be calculated using Equation 1. In some embodiments, the target level considered safe is the "target safe level" disclosed in Table A for the CYP3A4 substrate drug.

[0203]

[0205] In some embodiments, the CYP3A4 substrate drug is ranolazine. In some embodiments, ranolazine is indicated for chronic angina pectoris. In some embodiments, the standard dose for treating chronic angina pectoris is in the range of 500 to 1000 mg. In some embodiments, the standard dose is administered twice daily. In embodiments where the CYP3A4 substrate drug is ranolazine, the daily dose of ranolazine is about 500 mg or less, for example, about 490 mg, about 480 mg, about 470 mg, about 460 mg, about 450 mg, about 440 mg, about 430 mg, about 420 mg, about 410 mg, about 400 mg, about 390 mg, about 380 mg, about 370 mg, 360 mg, about 350 mg, about 340 mg, about 330 mg, about 320 mg, about 310 mg, about 300 mg, about 290 mg, about 280 mg, about 270 mg, 260 mg, about 250 mg, about 2 40 mg, about 230 mg, about 220 mg, about 210 mg, about 100 mg, about 190 mg, about 180 mg, about 170 mg, 160 mg, about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, or about 50 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0204]

[0206] In some embodiments, the CYP3A4 substrate drug is lurasidone. In some embodiments, lurasidone is indicated for the treatment of schizophrenia in adults and adolescents (13-17 years of age), depressive episodes associated with bipolar disorder type I (bipolar depression) in adults, moderate bipolar depression, severe bipolar depression, and severe bipolar depression with acute suicidal ideation and behavior (ASIB), either as monotherapy or adjunctive therapy with lithium or valproate. In some embodiments, the standard dose for treating schizophrenia in adults is in the range of 40-160 mg per day (e.g., 40, 60, 80, 100, 120, 140, 160, or 180 mg). In some embodiments, the standard dose for treating schizophrenia in adolescents (13-17 years of age) is in the range of 48-80 mg per day (e.g., 40, 60, or 80 mg). In some embodiments, the standard dose for treating bipolar depression in adults is in the range of 20-120 mg (e.g., 20, 40, 60, 80, 100, or 120 mg). In some embodiments, the standard dose for treating bipolar depression in pediatric patients (10-17 years old) is in the range of 20-80 mg (e.g., 20, 40, 60, or 80 mg). In embodiments where the CYP3A4 substrate drug is lurasidone, the daily dose of lurasidone is about 80 mg or less, e.g., about 75, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg (including all ranges and subranges thereof), with treatment postponed for at least about 2 to 42 days after discontinuing the posaconazole regimen, or the dose reduced for about 2 to 42 days after discontinuing the posaconazole regimen.

[0205]

[0207] In embodiments where the CYP3A4 substrate drug is tadalafil, The daily dose of posaconazole is about 2.5 mg or less, e.g., about 2.25 mg, about 2.0 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0206]

[0208] In other embodiments where the CYP3A4 substrate drug is tadalafil, The dose of fill per 72 hours is about 10 mg or less, for example, about 9.5 mg, about 9.0 mg , about 8.5 mg, about 8.0 mg, about 7.5 mg, about 7.0 mg, about 6.5 mg, about 6.0 mg, about 5.5 mg, about 5.0 mg, about 4.5 mg, about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0207]

[0209] In some embodiments, the CYP3A4 substrate drug is erlotinib. In some embodiments, the standard dose for treating non-small cell lung cancer (NSCLC) is 150 mg per day. In some embodiments, the standard dose for treating pancreatic cancer is 100 mg per day. In embodiments where the CYP3A4 substrate drug is erlotinib, the daily dose of erlotinib is about 150 mg or less, e.g., about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, or about 10 mg (including all ranges and subranges), with treatment postponed for at least 2 to 42 days after discontinuing the posaconazole regimen, or the dose reduced for about 2 to 42 days after discontinuing the posaconazole regimen.

[0208]

[0210] In some embodiments, the CYP3A4 substrate drug is solifenacin succinate. and the daily dose of solifenacin succinate is about 10 mg or less, e.g., about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, or about 0.5 mg, including all ranges and subranges thereof, with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0209]

[0211] In some embodiments, the CYP3A4 substrate drug is everolimus, The daily dose of verolimus is about 10 mg or less, e.g., about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0210]

[0212] In some embodiments, the CYP3A4 substrate drug is abemaciclib; The daily dose of abemaciclib is about 400 mg or less, e.g., about 350 mg, about 300 mg, about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg (including all ranges and subranges), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0211]

[0213] In some embodiments, the CYP3A4 substrate drug is ivacaftor. The daily dose of ivacaftor is about 300 mg or less, e.g., about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0212]

[0214] In some embodiments, the CYP3A4 substrate drug is ruxolitinib or its A pharmaceutically acceptable salt (e.g., ruxolitinib phosphate) is administered at a daily dose of about 50 mg or less, e.g., about 48 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 5 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0213]

[0215] In some embodiments, the CYP3A4 substrate drug is brexpiprazole. and the daily dose of brexpiprazole is about 4 mg or less, e.g., about 3 mg, about 2 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg (including all ranges and subranges thereof), and treatment is postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0214]

[0216] In some embodiments, the CYP3A4 substrate drug is ivacaftor / tezafenib. and the daily dose of tezacaftor is about 100 mg or less, e.g., about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 17.5 mg, about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, or about 5 mg (including all ranges and subranges thereof), and the daily dose of ivacaftor is about 300 mg or less, e.g., about 290 mg, about 280 mg, mg, about 270 mg, about 260 mg, about 250 mg, about 240 mg, about 230 mg, about 220 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, or about 50 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0215]

[0217] In some embodiments, the CYP3A4 substrate drug is regorafenib; The daily dose of regorafenib is about 160 mg or less, e.g., about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 25 mg, about 10 mg, or about 5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0216]

[0218] In some embodiments, the CYP3A4 substrate drug is daclatasvir; The daily dose of daclatasvir is about 90 mg or less, e.g., about 80 mg, about 70 mg, about 60 mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 17.5 mg, about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, or about 5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0217]

[0219] In some embodiments, the CYP3A4 substrate drug is crizotinib, The daily dose of rizotinib is about 500 mg or less, e.g., about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0218]

[0220] In some embodiments, the CYP3A4 substrate drug is naloxegol or a derivative thereof. and a physiologically acceptable salt (e.g., naloxegol oxalate) of naloxegol oxalate, wherein the daily dose of naloxegol oxalate is about 25 mg or less, e.g., about 22 mg, about 20 mg, about 18 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 10 mg, about 8 mg, about 5 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0219]

[0221] In some embodiments, the CYP3A4 substrate drug is dabrafenib; The daily dose of dabrafenib is about 300 mg or less, e.g., about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, or about 50 mg, about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0220]

[0222] In some embodiments, the CYP3A4 substrate drug is elbasvir or grazovir. and the daily dose of elbasvir is about 1000 mg or less, e.g., about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, or about 25 mg (including all ranges and subranges thereof), and the daily dose of grazoprevir is about 2000 mg or less, e.g., about 1500 mg, about 1250 mg, about 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200 mg, about 150 mg, about 100 mg, about 75 mg, or about 50 mg (including all ranges and subranges thereof), with treatment postponed for at least 2 to 42 days after discontinuation of the posaconazole regimen or with the dose reduced for about 2 to 42 days after discontinuation of the posaconazole regimen.

[0221]

[0223] In addition to the previous embodiments, the following embodiments are directed to specific CYP3A4 groups of the present disclosure. The method of administering a drug is further exemplified.

[0222]

[0224] In some embodiments, the CYP3A4 substrate drug is abemaciclib. The disease or condition treated with abemaciclib may include those described herein or those for which abemaciclib is indicated. For example, in some embodiments, abemaciclib is indicated for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine therapy. In some embodiments, abemaciclib is indicated for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression after endocrine therapy in combination with fulvestrant. In some embodiments, abemaciclib is indicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy and prior chemotherapy in the metastatic setting. Abemaciclib may be administered in dosage forms of 50 mg, 100 mg, 150 mg, or 200 mg. In some embodiments, abemaciclib is administered twice daily up to a total daily dose of 400 mg. For example, when abemaciclib is indicated for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine therapy, the reference dose is 150 mg, administered twice daily (reference daily total dose of 300 mg). When bemaciclib is indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression after endocrine therapy, the reference dose is 150 mg, administered twice daily (reference total daily dose 300 mg).When abemaciclib is indicated in combination with fulvestrant as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy and prior chemotherapy in the metastatic setting, the reference dose is 200 mg, administered twice daily (reference total daily dose 400 mg).Thus, in various embodiments, the reference total daily dose of abemaciclib can be, for example, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg. According to certain embodiments of the present disclosure, if the reference total daily dose of abemaciclib is, for example, 400 mg, the patient receives a reduced total daily dose of abemaciclib (either concurrently with posaconazole or after a delay period after discontinuing posaconazole). In some embodiments, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, or 350 mg (including all integers and ranges therebetween). When the reference total daily dose of abemaciclib is 400 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, or 375 mg (including all integers and ranges therebetween).When the reference total daily dose of abemaciclib is 350 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, or 325 mg (including all integers and ranges therebetween).If the reference total daily dose of abemaciclib is 300 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, or 275 mg (including all integers and ranges therebetween). If the reference total daily dose of abemaciclib is 250 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or 225 mg (including all integers and ranges therebetween). When the reference total daily dose of abemaciclib is 200 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg (including all integers and ranges therebetween). When the reference total daily dose of abemaciclib is 150 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg (including all integers and ranges therebetween). When the reference total daily dose of abemaciclib is 100 mg, the reduced total daily dose of abemaciclib is, for example, 25 mg, 50 mg, or 75 mg (including all integers and ranges therebetween). Similarly, if the individual reference dose of abemaciclib is 200 mg, the reduced individual reference dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 175 mg (including all integers and ranges therebetween). If the individual reference dose of abemaciclib is 150 mg, the reduced individual reference dose of abemaciclib is, for example, 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg (including all integers and ranges therebetween).

[0223]

[0225] In some embodiments, the CYP3A4 substrate drug is trastuzumab emtazobium. The drug is ado-trastuzumab emtansine. The disease or condition to which trastuzumab emtansine is directed may include any disease or condition described herein or any disease or condition for which trastuzumab emtansine is indicated. For example, in some embodiments, trastuzumab emtansine may be administered to patients previously treated with trastuzumab and a taxane, either separately or in combination. Trastuzumab emtansine is indicated as a single agent for the treatment of patients with HER-2-positive metastatic breast cancer. Patients must have previously been treated for metastatic disease or have developed disease recurrence during or within six months of completing adjuvant therapy. Trastuzumab emtansine may be administered via intravenous infusion at dosages of 2.4 mg / kg, 3 mg / kg, or 3.6 mg / kg. In some embodiments, trastuzumab emtansine is administered once every three weeks, up to a total dose of 3.6 mg every three weeks. For example, if trastuzumab emtansine is indicated as a single agent for the treatment of patients with HER-2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, either separately or in combination, and patients must have previously been treated for metastatic disease or developed recurrent disease during or within 6 months of completing adjuvant therapy, the reference dose is 3.6 mg / kg every 3 weeks (reference total dose is 3.6 mg / kg every 3 weeks). Thus, in various embodiments, the reference total daily dose of trastuzumab emtansine can be, for example, 0.3 mg / kg every 3 weeks, 0.6 mg / kg every 3 weeks, 0.9 mg / kg every 3 weeks, 1.2 mg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, 1.8 mg / kg every 3 weeks, 2.1 mg / kg every 3 weeks, 2.4 mg / kg every 3 weeks, 2.7 mg / kg every 3 weeks, 3.0 mg / kg every 3 weeks, 3.3 mg / kg every 3 weeks, or 3.6 mg / kg every 3 weeks. According to certain embodiments of the present disclosure, when the reference total daily dose of trastuzumab emtansine is, for example, 3.6 mg every 3 weeks, the patient receives a reduced total daily dose of trastuzumab emtansine (either concurrently with posaconazole or after a delay period after discontinuing posaconazole).In some embodiments, the reduced total daily dose of trastuzumab emtansine is, for example, 0.3 mg / kg every 3 weeks, 0.6 mg / kg every 3 weeks, 0.9 mg / kg every 3 weeks, 1.2 mg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, 1.8 mg / kg every 3 weeks, 2.1 mg / kg every 3 weeks, 2.4 mg / kg every 3 weeks, 2.7 mg / kg every 3 weeks, 3.0 mg / kg every 3 weeks, or 3.3 mg / kg every 3 weeks (including all integers and ranges therebetween). If the total daily dose of trastuzumab emtansine is 3.6 mg / kg every 3 weeks, then reduced reference total daily doses of trastuzumab emtansine are, for example, 0.3 mg / kg every 3 weeks, 0.6 mg / kg every 3 weeks, 0.9 mg / kg every 3 weeks, 1.2 mg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, 1.8 mg / kg every 3 weeks, 2.1 mg / kg every 3 weeks, 2.4 mg / kg every 3 weeks, 2.7 mg / kg every 3 weeks, 3.0 mg / kg every 3 weeks, and 3.3 mg / kg every 3 weeks (including all integers and ranges therebetween). If the total daily dose of trastuzumab emtansine is 3.0 mg / kg every 3 weeks, then the reduced reference total daily dose of trastuzumab emtansine is, for example, 0.3 mg / kg every 3 weeks, 0.6 mg / kg every 3 weeks, 0.9 mg / kg every 3 weeks, 1.2 mg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, 1.8 mg / kg every 3 weeks, 2.1 mg / kg every 3 weeks, 2.4 mg / kg every 3 weeks, or 2.7 mg / kg every 3 weeks (including all integers and ranges therebetween). If the total daily dose of trastuzumab emtansine is 2.4 mg / kg every 3 weeks, then the reduced reference total daily dose of trastuzumab emtansine is, for example, 0.3 mg / kg every 3 weeks, 0.6 mg / kg every 3 weeks, 0.9 mg / kg every 3 weeks, 1.2 mg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, 1.8 mg / kg every 3 weeks, or 2.1 mg / kg every 3 weeks (including all integers and ranges therebetween).

[0224]

[0226] In some embodiments, the CYP3A4 substrate drug is apalutamide. The disease or condition to be treated by palutamide may include the disease or condition described herein or the disease or condition for which apalutamide is indicated. For example, in some embodiments, apalutamide is indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer. Apalutamide may be administered in a dosage form of 60 mg. In some embodiments, apalutamide is administered in a dosage form of 1 It is administered once a day up to a total daily dose of 240 mg. For example, when apalutamide is used to treat patients with non-metastatic castration-resistant prostate cancer, the standard dose is 240 mg and is administered once a day (the standard daily dose is 240 mg). Thus, in various embodiments, the standard daily dose of apalutamide can be, for example, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, or 240 mg. According to certain embodiments of the present disclosure, when the standard daily dose of apalutamide is, for example, 240 mg, the patient takes a reduced total daily dose of apalutamide (either simultaneously with posaconazole or after a delay period after discontinuing posaconazole). In some embodiments, the reduced total daily dose of apalutamide is, for example, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, or 210 mg (including all integers and ranges therebetween). If the reference total daily dose of apalutamide is 240 mg, the reduced total daily dose of apalutamide is, for example, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, or 210 mg (including all integers and ranges therebetween). If the reference total daily dose of apalutamide is 180 mg, the reduced total daily dose of apalutamide is, for example, 30 mg, 60 mg, 90 mg, 120 mg, or 150 mg (including all integers and ranges therebetween). If the reference total daily dose of apalutamide is 120 mg, the reduced total daily dose of apalutamide is, for example, 30 mg, 60 mg, or 90 mg (including all integers and ranges therebetween). Similarly, if the individual reference dose of apalutamide is 60 mg, the reduced individual reference dose of apalutamide is, for example, 30 mg.

[0225]

[0227] In some embodiments, the CYP3A4 substrate drug is aripiprazole (ABILIFY®). Diseases or conditions treated with aripiprazole can include those described herein or those for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is indicated orally for schizophrenia. In some embodiments, aripiprazole is indicated orally for the acute treatment of manic and mixed episodes associated with bipolar disorder type I. In some embodiments, aripiprazole is indicated orally for the adjunctive treatment of major depressive disorder. In some embodiments, aripiprazole is indicated orally for hyperirritability associated with autistic disorder. In some embodiments, aripiprazole is indicated orally for the treatment of Tourette's syndrome. In some embodiments, aripiprazole is indicated by intramuscular injection for agitation associated with schizophrenia or bipolar mania. Aripiprazole can be administered in tablet dosage forms of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg, orally disintegrating tablets of 10 mg or 15 mg, a 1 mg / mL oral solution, or a 9.75 mg / 1.3 mL single-dose vial. In some embodiments, aripiprazole is administered once daily up to a total daily dose of 30 mg (orally or by injection). For example, when aripiprazole is indicated for the treatment of schizophrenia in adults, the initial standard dose is 10-15 mg, administered once daily (total daily dose is 10-15 mg). When aripiprazole is indicated for the treatment of schizophrenia in adults, the recommended standard dose is 10-15 mg, administered once daily (total daily dose is 10-15 mg). When aripiprazole is used for adult schizophrenia, the maximum standard dose is 30 mg, administered once daily (total standard daily dose is 30 mg). For example, when aripiprazole is used for adolescent schizophrenia, the initial standard dose is 2 mg, administered once daily (total standard daily dose is 2 mg). When aripiprazole is used for adolescent schizophrenia, the recommended standard dose is 10 mg, administered once daily (total standard daily dose is 10 mg).When aripiprazole is used for adolescent schizophrenia, the maximum standard dose is 30 mg, administered once daily (total standard daily dose is 30 mg). For example, when aripiprazole is used for adult bipolar mania (monotherapy), the initial standard dose is 15 mg, administered once daily (total standard daily dose is 15 mg). When aripiprazole is used for adult bipolar mania (monotherapy), the recommended standard dose is 15 mg, administered once daily (total standard daily dose is 15 mg). When aripiprazole is used for adult bipolar mania (monotherapy), the recommended standard dose is 15 mg, administered once daily (total standard daily dose is 15 mg). When aripiprazole is used as monotherapy, the maximum reference dose is 30 mg, administered once daily (total reference daily dose: 30 mg). For example, when aripiprazole is used for bipolar mania in adults (as an adjunct to lithium or valproate), the initial reference dose is 10-15 mg, administered once daily (total reference daily dose: 10-15 mg). When aripiprazole is used for bipolar mania in adults (as an adjunct to lithium or valproate), the recommended reference dose is 15 mg, administered once daily (total reference daily dose: 15 mg). When aripiprazole is used for bipolar mania in adults (as an adjunct to lithium or valproate), the maximum reference dose is 30 mg, administered once daily (total reference daily dose: 30 mg). For example, when aripiprazole is indicated for pediatric bipolar mania (monotherapy or adjunct to lithium or valproate), the initial reference dose is 2 mg, administered once daily (total reference daily dose: 2 mg). When aripiprazole is indicated for pediatric bipolar mania (monotherapy or adjunct to lithium or valproate), the recommended reference dose is 10 mg, administered once daily (total reference daily dose: 10 mg). When aripiprazole is indicated for pediatric bipolar mania (monotherapy or adjunct to lithium or valproate), the maximum reference dose is 30 mg, administered once daily (total reference daily dose: 30 mg). For example, when aripiprazole is indicated for adult major depressive disorder (adjunct to an antidepressant), the initial reference dose is 2-5 mg, administered once daily (total reference daily dose: 2-5 mg). When aripiprazole is indicated for major depressive disorder in adults (as an adjunct to an antidepressant), the recommended standard dose is 5-10 mg, administered once daily (total daily dose: 5-10 mg). When aripiprazole is indicated for major depressive disorder in adults (as an adjunct to an antidepressant), the maximum standard dose is 15 mg, administered once daily (total daily dose: 15 mg). For example, when aripiprazole is indicated for hypersensitivity associated with autistic disorder in pediatric patients, the initial standard dose is 2 mg, administered once daily (total daily dose: 2 mg).When aripiprazole is indicated for hypersensitivity associated with autistic disorder in pediatric patients, the recommended reference dose is 5 to 10 mg, administered once daily (total daily dose: 5 to 10 mg). When aripiprazole is indicated for hypersensitivity associated with autistic disorder in pediatric patients, the maximum reference dose is 15 mg, administered once daily (total daily dose: 15 mg). For example, when aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the initial reference dose is 2 mg, administered once daily (total daily dose: 2 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the recommended reference dose is 5 mg, administered once daily (total daily dose: 5 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the maximum reference dose is 10 mg, administered once daily (total daily dose: 10 mg). For example, when aripiprazole is used for Tourette's syndrome in patients weighing 50 kg or more, the initial standard dose is 2 mg, administered once daily (total standard daily dose: 2 mg). When aripiprazole is used for Tourette's syndrome in patients weighing 50 kg or more, the recommended standard dose is 10 mg, administered once daily (total standard daily dose: 10 mg). When aripiprazole is used for Tourette's syndrome in patients weighing 50 kg or more, the maximum standard dose is 20 mg, administered once daily (total standard daily dose: 20 mg). For example, when aripiprazole is used for agitation associated with schizophrenia or bipolar mania in adults, the initial standard dose is 9.75 mg / 1.3 mL, administered intramuscularly once daily (total standard daily dose: 9.75 mg / 1.3 mL). When aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania in adults, the maximum reference dose is 30 mg, administered intramuscularly once daily (total daily reference dose 30 mg).Thus, in various embodiments, the total daily reference dose of aripiprazole can be, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg. According to certain embodiments of the present disclosure, when the total daily reference dose of aripiprazole is, for example, 30 mg, the patient is administered a reduced dose of aripiprazole. The total daily dose of piprazole is taken (either simultaneously with posaconazole or after a delay period after discontinuing posaconazole). In some embodiments, the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg (including all integers and ranges therebetween). If the reference daily total dose of aripiprazole is 30 mg, then the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg (including all integers and ranges therebetween). When the reference daily total dose of aripiprazole is 20 mg, the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, or 19 mg (including all integers and ranges therebetween).When the reference daily total dose of aripiprazole is 15 mg, the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, or 14 mg (including all integers and ranges therebetween). If the reference total daily dose of aripiprazole is 10 mg, the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg (including all integers and ranges therebetween).If the reference total daily dose of aripiprazole is 5 mg, the reduced total daily dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, or 4 mg (including all integers and ranges therebetween).When the standard daily dose of aripiprazole is 2 mg, the reduced standard daily dose of aripiprazole is, for example, 1 mg. Similarly, when the standard individual dose of aripiprazole is 30 mg, the reduced standard individual dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, or 29 mg (including all integers and ranges therebetween). When the individual reference dose of aripiprazole is 20 mg, the reduced individual reference dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, or 19 mg (including all integers and ranges therebetween).When the individual reference dose of aripiprazole is 10 mg, the reduced individual reference dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg (including all integers and ranges therebetween).When the individual reference dose of aripiprazole is 5 mg, the reduced individual reference dose of aripiprazole is, for example, 1 mg, 2 mg, 3 mg, or 4 mg (including all integers and ranges therebetween). If the individual reference dose of aripiprazole is 2 mg, the reduced individual reference dose of aripiprazole is, for example, 1 mg.

[0226]

[0228] In some embodiments, the CYP3A4 substrate drug is aripiprazole (ARISTADA®). Diseases or conditions treated with aripiprazole are described herein. The diseases or conditions described in the preceding paragraphs may include those described in the preceding paragraphs, or diseases or conditions for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is indicated for schizophrenia. Aripiprazole may be administered in a single-use pre-filled syringe in tablet dosage form of 441 mg, 662 mg, 882 mg, or 1064 mg. In some embodiments, aripiprazole is administered once a month at a maximum total dose of 882 mg. In some embodiments, aripiprazole is administered once every six weeks at a maximum total dose of 882 mg. In some embodiments, aripiprazole is administered once every two months at a maximum total dose of 1064 mg. For example, when aripiprazole is used for schizophrenia, the standard dose is 441 mg, 662 mg, or 882 mg administered once a month, 882 mg administered once every six weeks, or 1064 mg administered once every two months (standard total doses are 441 mg per month, 662 mg per month, 882 mg per month, 882 mg every six weeks, or 1064 mg every two months). Thus, in various embodiments, the standard total dose of aripiprazole can be, for example, 441 mg per month, 662 mg per month, 882 mg per month, 882 mg every six weeks, or 1064 mg every two months. According to certain embodiments of the present disclosure, if the baseline total daily dose of aripiprazole is, for example, 1064 mg every two months, the patient takes a reduced total daily dose of aripiprazole (either concurrently with posaconazole or after a delay period after discontinuing posaconazole). In some embodiments, the reduced total daily dose of aripiprazole is, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 120 mg per month, 140 mg per month, 160 mg per month, 180 mg per month, 200 mg per month, 220 mg per month, 240 mg per month, 260 mg per month, 280 mg per month, 300 mg per month, 320 mg per month, 340 mg per month, 360 mg per month, 380 mg per month, 400 mg per month, 420 mg per month, 440 mg per month, 460 mg per month, 480 mg per month, 490 mg per month, 500 mg per month, 510 mg per month, 520 mg per month, 530 mg per month, 540 mg per month, 550 mg per month, 560 mg per month, 570 mg per month, 580 mg per month, 590 mg per month, 600 mg per month, 610 mg per month, 620 mg per month, 630 mg per month, 640 mg per month, 650 mg per month, 660 mg per month, 670 mg per month, 680 mg per month, 690 mg per month, 700 mg per month, 710 mg per month, 720 mg per month, 730 mg per month, 740 mg per month, 750 mg per month, 760 mg per month, 770 mg per month, 780 mg per month, 790 mg per month, 800 mg per month, 810 mg per month, 820 400mg per month, 420mg per month, 440mg per month, 460mg per month, 480mg per month, 500mg per month, 520mg per month, 540mg per month, 560mg per month, 580mg per month, 600mg per month, 620mg per month, 640mg per month, 660mg per month, 680mg per month, 700mg per month, 720mg per month, 740mg per month, 760mg per month, 780mg per month, 800mg per month, 820mg per month, 840mg per month, 860mg per month, or 880mg per month (including all integers and ranges therebetween);Alternatively, 10mg for 6 weeks, 20mg for 6 weeks, 30mg for 6 weeks, 40mg for 6 weeks, 50mg for 6 weeks, 60mg for 6 weeks, 70mg for 6 weeks, 80mg for 6 weeks, 90mg for 6 weeks, 100mg for 6 weeks, 120mg for 6 weeks, 140mg for 6 weeks, 160mg for 6 weeks, 180mg for 6 weeks, 200mg for 6 weeks, 220mg for 6 weeks, 240mg for 6 weeks, 260mg for 6 weeks, 280mg for 6 weeks, 300mg for 6 weeks, 320mg for 6 weeks, 340mg for 6 weeks, 360mg for 6 weeks, 380mg for 6 weeks, 400mg for 6 weeks, 4 20 mg every 6 weeks, 440 mg every 6 weeks, 460 mg every 6 weeks, 480 mg every 6 weeks, 500 mg every 6 weeks, 520 mg every 6 weeks, 540 mg every 6 weeks, 560 mg every 6 weeks, 580 mg every 6 weeks, 600 mg every 6 weeks, 620 mg every 6 weeks, 640 mg every 6 weeks, 660 mg every 6 weeks, 680 mg every 6 weeks, 700 mg every 6 weeks, 720 mg every 6 weeks, 740 mg every 6 weeks, 760 mg every 6 weeks, 780 mg every 6 weeks, 800 mg every 6 weeks, 820 mg every 6 weeks, 840 mg every 6 weeks, 860 mg every 6 weeks, or 880 mg every 6 weeks (all integers and increments therebetween) ranges); or 10mg every 2 months, 20mg every 2 months, 30mg every 2 months, 40mg every 2 months, 50mg every 2 months, 60mg every 2 months, 70mg every 2 months, 80mg every 2 months, 90mg every 2 months, 100mg every 2 months, 120mg every 2 months, 140mg every 2 months, 160mg every 2 months, 180mg every 2 months, 200mg every 2 months, 220mg every 2 months, 240mg every 2 months, 260mg every 2 months, 280mg every 2 months, 300mg every 2 months, 320mg every 2 months, 340mg every 2 months, 360mg every 2 months, 380mg every 2 months, 400mg every 2 months g, 420mg in 2 months, 440mg in 2 months, 460mg in 2 months, 480mg in 2 months, 500mg in 2 months, 520mg in 2 months, 540mg in 2 months, 560mg in 2 months, 580mg in 2 months, 600mg in 2 months, 620mg in 2 months, 640mg in 2 months, 660mg in 2 months, 680mg in 2 months, 700mg in 2 months, 720mg in 2 months, 740mg in 2 months, 760mg in 2 months, 780mg in 2 months, 800mg in 2 months, 820mg in 2 months, 840mg in 2 months, 860mg in 2 months, 880mg in 2 months, 900mg in 2 months;g, 920 mg every 2 months, 940 mg every 2 months, 960 mg every 2 months, 180 mg every 2 months, 200 mg every 2 months, 220 mg every 2 months, 240 mg every 2 months, 960 mg every 2 months, 980 mg every 2 months, 1000 mg every 2 months, 1020 mg every 2 months, 1040 mg every 2 months, or 1060 mg every 2 months (including all integers and ranges therebetween). If the standard total dose of aripiprazole is 1064 mg for 2 months, the reduced total dose of aripiprazole can be, for example, 10 mg for 2 months, 20 mg for 2 months, 30 mg for 2 months, 40 mg for 2 months, 50 mg for 2 months, 60 mg for 2 months, 70 mg for 2 months, 80 mg for 2 months, 90 mg for 2 months, 100 mg for 2 months, 120 mg for 2 months, 140 mg for 2 months, 160 mg for 2 months, 170 mg for 2 months, 180 mg for 2 months, 190 mg for 2 months, 200 mg for 2 months, 210 mg for 2 months, 220 mg for 2 months, 230 mg for 2 months, 240 mg for 2 months, 250 mg for 2 months, 260 mg for 2 months, 270 mg for 2 months, 280 mg for 2 months, 290 mg for 2 months, 300 mg for 2 months, 310 mg for 2 months, 320 mg for 2 months, 330 mg for 2 months, 340 mg for 2 months, 350 mg for 2 months, 360 mg for 2 months, 370 mg for 2 months, 380 mg for 2 months, 390 mg for 2 months, 400 mg for 2 months, 410 mg for 2 months, 420 mg for 2 months, 430 mg for 2 months, 440 mg for 2 months, 450 mg for 2 months, 460 mg for 2 months, 470 mg for 2 months, 480 mg for 2 months, 490 mg for 2 months, 500 mg for 2 months, 510 mg for 2 months, 180mg in 1 month, 200mg in 2 months, 220mg in 2 months, 240mg in 2 months, 260mg in 2 months, 280mg in 2 months, 300mg in 2 months, 320mg in 2 months, 340mg in 2 months, 360mg in 2 months, 380mg in 2 months, 400mg in 2 months, 420mg in 2 months, 440mg in 2 months, 460mg in 2 months, 480mg in 2 months, 500mg in 2 months, 520mg in 2 months mg, 540mg in 2 months, 560mg in 2 months, 580mg in 2 months, 600mg in 2 months, 620mg in 2 months, 640mg in 2 months, 660mg in 2 months, 680mg in 2 months, 700mg in 2 months, 720mg in 2 months, 740mg in 2 months, 760mg in 2 months, 780mg in 2 months, 800mg in 2 months, 820mg in 2 months, 840mg in 2 months, 860mg in 2 months 880 mg in 2 months, 900 mg in 2 months, 920 mg in 2 months, 940 mg in 2 months, 960 mg in 2 months, 180 mg in 2 months, 200 mg in 2 months, 220 mg in 2 months, 240 mg in 2 months, 960 mg in 2 months, 980 mg in 2 months, 1000 mg in 2 months, 1020 mg in 2 months, 1040 mg in 2 months, or 1060 mg in 2 months (including all integers and ranges therebetween).If the standard total dose of aripiprazole is 882 mg for 6 weeks, the reduced total dose of aripiprazole can be, for example, 10 mg for 6 weeks, 20 mg for 6 weeks, 30 mg for 6 weeks, 40 mg for 6 weeks, 50 mg for 6 weeks, 60 mg for 6 weeks, 70 mg for 6 weeks, 80 mg for 6 weeks, 90 mg for 6 weeks, 100 mg for 6 weeks, 120 mg for 6 weeks, 140 mg for 6 weeks, 160 mg for 6 weeks, 180 mg for 6 weeks, 200 mg for 6 weeks, 220 mg for 6 weeks, 240 mg for 6 weeks, 260 mg for 6 weeks, 280 mg for 6 weeks, 300 mg for 6 weeks, 320 mg for 6 weeks, 340 mg for 6 weeks, 360 mg for 6 weeks, 380 mg for 6 weeks, 390 mg for 6 weeks, 400 mg for 6 weeks, 410 mg for 6 weeks, 420 mg for 6 weeks, 430 mg for 6 weeks, 440 mg for 6 weeks, 450 mg for 6 weeks, 460 mg for 6 weeks, 470 mg for 6 weeks, 480 mg for 6 weeks, 490 mg for 6 weeks, 500 mg for 6 weeks, 510 mg for 6 weeks, 520 mg for 6 weeks, 530 mg for 6 weeks, 540 mg for 6 weeks, 550 mg for 6 weeks, 560 mg for 6 weeks, 570 mg for 6 weeks, 580 mg for 6 weeks, 590 mg for 6 weeks, 600 mg for 6 weeks, 610 mg for 6 weeks, 620 mg for 6 weeks, 6 0 mg every 6 weeks, 400 mg every 6 weeks, 420 mg every 6 weeks, 440 mg every 6 weeks, 460 mg every 6 weeks, 480 mg every 6 weeks, 500 mg every 6 weeks, 520 mg every 6 weeks, 540 mg every 6 weeks, 560 mg every 6 weeks, 580 mg every 6 weeks, 600 mg every 6 weeks, 620 mg every 6 weeks, 640 mg every 6 weeks, 660 mg every 6 weeks, 680 mg every 6 weeks, 700 mg every 6 weeks, 720 mg every 6 weeks, 740 mg every 6 weeks, 760 mg every 6 weeks, 780 mg every 6 weeks, 800 mg every 6 weeks, 820 mg every 6 weeks, 840 mg every 6 weeks, 860 mg every 6 weeks, or 880 mg every 6 weeks (including all integers and ranges therebetween).If the standard total dose of aripiprazole is 882 mg per month, the reduced total dose of aripiprazole can be, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 120 mg per month, 140 mg per month, 160 mg per month, 180 mg per month, 200 mg per month, 220 mg per month, 240 mg per month, 260 mg per month, 280 mg per month, 300 mg per month, 320 mg per month, 340 mg per month, 360 mg per month, 380 mg per month, 400 mg per month, 420 mg per month, 440 mg per month, 460 mg per month, 480 mg per month, 490 mg per month, 500 mg per month, 510 mg per month, 520 mg per month, 530 mg per month, 540 mg per month, 550 mg per month, 560 mg per month, 570 mg per month, 580 mg per month, 590 mg per month, 600 mg per month, 610 mg per month, 620 mg per month, 630 mg per month, 640 mg per month, 650 mg per month, 660 mg per month, 670 mg per month, 680 mg per month, 690 mg per month, 700 mg per month, 710 mg per month, 720 mg per month, 730 mg per month, 740 mg per month, 750 mg per month, 760 mg per month, 770 mg per month, 780 mg per month, 790 mg per month, 800 0 mg per month, 400 mg per month, 420 mg per month, 440 mg per month, 460 mg per month, 480 mg per month, 500 mg per month, 520 mg per month, 540 mg per month, 560 mg per month, 580 mg per month, 600 mg per month, 620 mg per month, 640 mg per month, 660 mg per month, 680 mg per month, 700 mg per month, 720 mg per month, 740 mg per month, 760 mg per month, 780 mg per month, 800 mg per month, 820 mg per month, 840 mg per month, 860 mg per month, or 880 mg per month (including all integers and ranges therebetween). If the daily dose is 62 mg, the reduced total dose of aripiprazole is, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 120 mg per month, 140 mg per month, 160 mg per month, 180 mg per month, 200 mg per month, 220 mg per month, 240 mg per month, 260 mg per month, 280 mg per month, 290 mg per month, 300 mg per month, 310 mg per month, 320 mg per month, 330 mg per month, 340 mg per month, 350 mg per month, 360 mg per month, 370 mg per month, 380 mg per month, 390 mg per month, 400 mg per month, 410 mg per month, 420 mg per month, 430 mg per month, 440 mg per month, 450 mg per month, 460 mg per month, 470 mg per month, 480 mg per month, 490 mg per month, 500 mg per month, 510 mg per month, 520 mg per month, 530 mg per month, 540 mg per month, 550 mg per month, 560 mg per month, 570 mg per month, 580 mg per month, 590 mg per month, 600 mg per month, 610 mg per month, 620 mg per month, 630 mg per month, 640 mg per month, 650 mg per month, 660 mg per month, 670 mg per month, 680 mg per month, 690 mg per month, 700 mg per month, 710 mg per month 300mg per month, 320mg per month, 340mg per month, 360mg per month, 380mg per month, 400mg per month, 420mg per month, 440mg per month, 460mg per month, 480mg per month, 500mg per month, 520mg per month, 540mg per month, 560mg per month, 580mg per month, 600mg per month, 620mg per month, 640mg per month, or 660mg per month (including all integers and ranges therebetween). If the standard total dose of aripiprazole is 441 mg per month, the reduced total dose of aripiprazole can be, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 120 mg per month, 140 mg per month, 160 mg per month, 180 mg per month, 190 mg per month, 200 mg per month, 210 mg per month, 220 mg per month, 230 mg per month, 240 mg per month, 250 mg per month, 260 mg per month, 270 mg per month, 280 mg per month, 290 mg per month, 300 mg per month, 310 mg per month, 320 mg per month, 330 0 mg per month, 180 mg per month, 200 mg per month, 220 mg per month, 240 mg per month, 260 mg per month, 280 mg per month, 300 mg per month, 320 mg per month, 340 mg per month, 360 mg per month, 380 mg per month, 400 mg per month, 420 mg per month, or 440 mg per month (including all integers and ranges therebetween).

[0227]

[0229] In some embodiments, the CYP3A4 substrate drug is aripiprazole (ABILIFY MAINTENA®). Diseases or conditions treated with aripiprazole include: The diseases or conditions may include those described herein or those for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is indicated for the treatment of schizophrenia in adults. In some embodiments, aripiprazole is indicated as a maintenance monotherapy treatment for bipolar disorder type I in adults. Aripiprazole may be administered in 160, 200 mg, 300 mg, or 400 mg injections. In some embodiments, aripiprazole is administered once a month up to a total daily dose of 400 mg. For example, when aripiprazole is indicated for schizophrenia in adults, the reference dose is 400 mg, administered once a month (a total daily reference dose of 400 mg per month). For example, when aripiprazole is indicated for the maintenance monotherapy treatment of bipolar disorder type I in adults, the reference dose is 400 mg, administered once a month (a total daily reference dose of 400 mg per month). Thus, in various embodiments, the baseline total dose of aripiprazole can be, for example, 160 mg per month, 200 mg per month, 300 mg per month, or 400 mg per month. According to certain embodiments of the present disclosure, if the baseline total daily dose of aripiprazole is, for example, 400 mg per month, the patient takes a reduced total daily dose of aripiprazole (either concurrently with posaconazole or after a delay period after discontinuing posaconazole).In some embodiments, the reduced total dose of aripiprazole is, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 110 mg per month, 120 mg per month, 130 mg per month, 140 mg per month, 150 mg per month, 160 mg per month, 170 mg per month, 180 mg per month, 190 mg per month, 200 mg per month, 210 mg per month, 220 mg per month, 230 mg per month, 240 mg per month, 250 mg per month, 260 mg per month, 270 mg per month, 280 mg per month, 290 mg per month, 300 mg per month, 310 mg per month, 320 mg per month, 330 mg per month, 340 mg per month, 350 mg per month, 360 mg per month, 370 mg per month, 380 mg per month, 390 mg per month, 400 mg per month, 410 mg per month, 420 mg per month, 430 mg per month, 440 mg per month, 450 mg per month, 460 mg per month, 470 mg per month, 480 mg per month, 490 mg per month, 500 mg per month, 510 mg per month, 520 mg per month, 530 mg per month, 540 mg per month, 550 mg per month, 560 mg per month, 570 mg per month, 580 mg per month, 590 mg per month, 600 mg per month, 610 mg per month, 620 mg per month, 630 mg If the standard total dose of aripiprazole is 400 mg per month, the reduced total dose of aripiprazole is 10 mg per month, 20 mg per month, 210 mg per month, 220 mg per month, 230 mg per month, 240 mg per month, 250 mg per month, 260 mg per month, 270 mg per month, 280 mg per month, 290 mg per month, 300 mg per month, 310 mg per month, 320 mg per month, 330 mg per month, 340 mg per month, 350 mg per month, 360 mg per month, 370 mg per month, 380 mg per month, or 390 mg per month. 30mg per month, 40mg per month, 50mg per month, 60mg per month, 70mg per month, 80mg per month, 90mg per month, 100mg per month, 110mg per month, 120mg per month, 130mg per month, 140mg per month, 150mg per month, 160mg per month, 170mg per month, 180mg per month, 190mg per month, 200mg per month, 210mg per month, 220mg per month, 230mg per month, 240mg per month, 250mg per month, 260mg per month, 270mg per month, 280mg per month, 290mg per month, 300mg per month, 310mg per month, 320mg per month, 330mg per month, 340mg per month, 350mg per month, 360mg per month, 370mg per month, 380mg per month, or 390mg per month (including all integers and ranges therebetween). If the standard total dose of aripiprazole is 300 mg per month, the reduced total dose of aripiprazole can be, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 110 mg per month, 120 mg per month, 130 mg per month, 140 mg per month, 150 mg per month, 160 mg per month, 170 mg per month, 180 mg per month, 190 mg per month, 200 mg per month, 210 mg per month, 220 mg per month, 230 mg per month, 240 mg per month, 250 mg per month, 260 mg per month, 270 mg per month, 280 mg per month, 290 mg per month, 300 mg per month, 310 mg per month, 320 mg per month, 330 mg per month, 340 mg per month, 350 mg per month, 360 mg per month, 370 mg per month, 380 mg per month, 390 mg per month, 400 mg per month, 410 mg per month, 420 mg per month, 430 mg per month, 440 mg per month, 450 mg per month, 460 mg per month, 470 mg per month, 480 mg per month, 490 mg per month, 500 mg per month, 510 mg per month, 520 mg per month, 530 mg per month, 540 mg per month, 550 mg per month, 560 mg per month, 570 mg per month, 580 mg per month, 590 mg per month, 600 mg per month, 610 0 mg per month, 150 mg per month, 160 mg per month, 170 mg per month, 180 mg per month, 190 mg per month, 200 mg per month, 210 mg per month, 220 mg per month, 230 mg per month, 240 mg per month, 250 mg per month, 260 mg per month, 270 mg per month, 280 mg per month, or 290 mg per month (including all integers and ranges therebetween).If the reference total dose of aripiprazole is 200 mg per month, the reduced total dose of aripiprazole is, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 110 mg per month, 120 mg per month, 130 mg per month, 140 mg per month, 150 mg per month, 160 mg per month, 170 mg per month, 180 mg per month, or 190 mg per month (including all integers and ranges therebetween). If the reference total dose of aripiprazole is 160 mg per month, the reduced total dose of aripiprazole is, for example, 10 mg per month, 20 mg per month, 30 mg per month, 40 mg per month, 50 mg per month, 60 mg per month, 70 mg per month, 80 mg per month, 90 mg per month, 100 mg per month, 110 mg per month, 120 mg per month, 130 mg per month, 140 mg per month, or 150 mg per month, 160 mg per month (including all integers and ranges therebetween).

[0228]

[0230] In some embodiments, the CYP3A4 substrate drug is bosutinib. Diseases or conditions treated with bosutinib may include those described herein or those for which bosutinib is indicated. For example, in some embodiments, bosutinib is indicated for newly diagnosed chronic phase Ph+ chronic myeloid leukemia (CML). In some embodiments, bosutinib is indicated for chronic phase, accelerated phase, or acute phase Ph+ CML with resistance or intolerance to previous therapy. Bosutinib can be administered in dosage forms of 100 mg, 400 mg, or 500 mg. In some embodiments, bosutinib is administered once daily up to a total daily dose of 600 mg. For example, when bosutinib is indicated for newly diagnosed chronic phase Ph+ chronic myeloid leukemia (CML), the standard dose is 400 mg, administered once daily (the standard total daily dose is 400 mg). For example, when bosutinib is indicated for chronic-phase, accelerated-phase, or acute-phase Ph+ CML with resistance or intolerance to previous therapy, the reference dose is 500 mg administered once daily (a reference total daily dose of 500 mg). In some embodiments, in patients who have not achieved a complete hematologic, cytogenetic, or molecular response and have no adverse reactions of grade 3 or higher, the dose is titrated in increments of 100 mg once daily to a maximum of 600 mg daily. Thus, in various embodiments, the reference total daily dose of bosutinib can be, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. According to certain embodiments of the present disclosure, bosutinib is If the standard total daily dose of bosutinib is, for example, 600 mg, the patient receives a reduced total daily dose of bosutinib (either simultaneously with posaconazole or after a delay period after discontinuing posaconazole). In some embodiments, the reduced total daily dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 550 mg (including all integers and ranges therebetween). If the standard total daily dose of bosutinib is 600 mg, the reduced total daily dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 550 mg (including all integers and ranges therebetween). If the reference total daily dose of bosutinib is 500 mg, the reduced total daily dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg (including all integers and ranges therebetween). If the reference total daily dose of bosutinib is 400 mg, the reduced total daily dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg (including all integers and ranges therebetween). Similarly, if the individual reference dose of bosutinib is 500 mg, the reduced individual reference dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg (including all integers and ranges therebetween). If the individual reference dose of bosutinib is 400 mg, the reduced individual reference dose of bosutinib is, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg (including all integers and ranges therebetween).

[0229]

[0231] In some embodiments, the CYP3A4 substrate drug is brexpiprazole. The disease or condition treated with brexpiprazole may include any of the diseases or conditions described herein or any disease or condition for which brexpiprazole is indicated. For example, in some embodiments, brexpiprazole is indicated for use as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD). In some embodiments, brexpiprazole is indicated for the treatment of schizophrenia. Brexpiprazole may be administered in dosage forms of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. In some embodiments, brexpiprazole is administered once daily up to a total daily dose of 8 mg. For example, when brexpiprazole is indicated for use as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), the starting reference dose is 0.5 mg or 1 mg, administered once daily (total daily reference dose is 0.5 mg or 1 mg). When brexpiprazole is indicated for use as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), the recommended standard dose is 2 mg, administered once daily (total daily dose: 2 mg). When brexpiprazole is indicated for use as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), the maximum standard dose is 3 mg, administered once daily (total daily dose: 3 mg). For example, when brexpiprazole is indi...

Claims

1. 1. A composition comprising a CYP3A4 substrate drug for use in treating a patient in need thereof, comprising: The patient was treated with posaconazole, which included the following steps: (a) selecting a reference dose of the CYP3A4 substrate drug based on the age and / or condition of the patient; (b) discontinuing posaconazole treatment; (c) Wait at least 2 days after stopping posaconazole treatment; then (b) administering said CYP3A4 substrate drug as soon as it is safe to do so.

2. The CYP3A4 substrate drug is lurasidone, ranolazine, lumacaftor / ivacaftor, venetoclax, trabectedin, ribociclib succinate, deflazacort, cinacalcet hydrochloride, pimavanserin tartrate, aripiprazole lauroxyl, cariprazine hydrochloride, simeprevir sodium, everolimus, saxagliptin hydrochloride, saxagliptin / metformin hydrochloride, ticagrelor, vilazodone hydrochloride, apixaban, Tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloride monohydrate, dronedarone hydrochloride, fluticasone propionate / salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine, cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab ematansine, bosutinib Monohydrate, sunitinib malate, fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole, axitinib, dapagliflozin / saxagliptin, cabozantinib S-malate, ponatinib hydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide, pomalidomide, abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexitamide 2. The use of claim 1, wherein the agent is selected from the group consisting of cuspiprazole, ivacaftor / tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, elbasvir / grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

3. The CYP3A4 substrate drug is lumacaftor / ivacaftor, venetoclax, trabectedin, ribociclib succinate, deflazacort, cinacalcet hydrochloride, pimavanserin tartrate, aripiprazole lauroxyl, cariprazine hydrochloride, simeprevir sodium, everolimus, saxagliptin hydrochloride, saxagliptin / metformin hydrochloride, ticagrelor, vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloride monohydrate, dronedarone hydrochloride, fluticasone propionate / salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine, cabazitaxel, or tolvaptan , fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole, axitinib, dapagliflozin / saxagliptin, cabozantinib S-malate, ponatinib hydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide, pomalidomide, abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole, ivacaftor / tezacaftor, regorafenib, daclatasvir, crizotinib, na 2. The use of claim 1, wherein the medicament is selected from the group consisting of loxegoroxalate, dabrafenib, elbasvir / grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

4. The CYP3A4 substrate drug is cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole, axitinib, dapagliflozin / saxagliptin, cabozantinib S-malate, ponatinib hydrochloride, isavucazonium sulfate, lomitapide mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride, 2. The use of claim 1, wherein the medicament is selected from the group consisting of pimozide, pomalidomide, abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole, ivacaftor / tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, elbasvir / grazoprevir, apalutamide, brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

5. 2. The use of claim 1, wherein the CYP3A4 substrate drug is selected from the group consisting of cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant, solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine fumarate, maraviroc, pazopanib hydrochloride, aripiprazole, axitinib, dapagliflozin / saxagliptin, cabozantinib S-malate, ponatinib hydrochloride, isavuquazonium sulfate, lomitapide mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride, pimozide, and pomalidomide.

6. 2. The use of claim 1, wherein the CYP3A4 substrate drug is selected from the group consisting of abemaciclib, ivacaftor, olaparib, ruxolitinib phosphate, brexpiprazole, ivacaftor / tezacaftor, regorafenib, daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, and elbasvir / grazoprevir.

7. 2. The use of claim 1, wherein the CYP3A4 substrate drug is selected from the group consisting of apalutamide, brigatinib, cannabidiol, copanlisib, duvelisib, encorafenib, flibanserin, ivabradine, ivosidenib, panobinostat, sonidegib, and vemurafenib.

8. 8. The use according to any one of claims 1 to 7, wherein the CYP3A4 substrate drug is administered in step (d) as soon as at least one of the AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substrate does not exceed a maximal level at which the benefit of treating the patient outweighs the risks of high exposure to the CYP3A4 substrate drug.

9. The CYP3A4 substrate drug is 9. The use of any one of claims 1 to 8, wherein step (d) is administered as soon as at least one of AUC, GMR Cmax, or CYP3A4 substrate drug no longer exceeds the target safe level set forth in Table A for the CYP3A4 substrate drug.

10. The CYP3A4 substrate drug is administered on the day the CYP3A4 substrate drug is administered in step (d).

10. The use of any one of claims 1 to 9, wherein the CYP3A4 substrate is administered to achieve an AUC or Cmax of the CYP3A4 substrate that is at least about 105% of the predicted AUC or Cmax of the CYP3A4 substrate.

11. 11. The use of claim 10, wherein the AUC or Cmax of the CYP3A4 substrate is at least about 105% of the predicted AUC or Cmax on the day the CYP3A4 substrate drug is administered, but is below the target safety level disclosed in Table A for the CYP3A4 substrate drug.

12. The use according to any one of claims 1 to 9, wherein the CYP3A4 substrate drug is administered in step (d) to achieve a GMR AUC or GMR Cmax of the CYP3A4 substrate drug that is at least about 1.05-fold the expected AUC or Cmax.

13. 13. The use of claim 12, wherein the CYP3A4 substrate drug is administered in step (d) to achieve a GMR AUC or GMR Cmax of the CYP3A4 substrate drug that is at least about 1.05-fold the predicted AUC or Cmax on the day the CYP3A4 substrate drug is administered, but is below the target safety level disclosed in Table A for the CYP3A4 substrate drug.

14. The use according to any one of claims 1 to 13, wherein the waiting in step (c) is at least 5 days.

15. The use according to any one of claims 1 to 13, wherein the waiting in step (c) is at least 7 days.

16. The use according to any one of claims 1 to 13, wherein the waiting in step (c) is at least 14 days.

17. The use according to any one of claims 1 to 13, wherein the waiting in step (b) is in the range of 2 to 42 days.

18. The use according to any one of claims 1 to 13, wherein the waiting in step (b) is in the range of 5 to 42 days.

19. The use according to any one of claims 1 to 13, wherein the waiting in step (b) is in the range of 7 to 21 days.

20. The use according to any one of claims 1 to 13, wherein the waiting in step (b) is in the range of 14 to 28 days.

21. The patients include those with schizophrenia in adults and adolescents (13-17 years old), depressive episodes associated with bipolar disorder type I (bipolar depression) in adults and pediatric patients (10-17 years old) (monotherapy or adjunctive therapy with lithium or valproate), moderate bipolar depression, severe bipolar depression, and severe bipolar depression with acute suicidal ideation and behavior (ASIB), chronic angina pectoris, cystic fibrosis in patients aged 6 years or older who are homozygous for the F508del mutation in the CFTR gene, and at least one prior treatment. chronic lymphocytic leukemia in patients with a deletion of the short arm of chromosome 17 who have received a prior anthracycline-containing regimen; unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen; hormone receptor (HR)-positive advanced or metastatic breast cancer in postmenopausal women; human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer; negative advanced or metastatic breast cancer (in combination with an aromatase inhibitor for postmenopausal women); Duchenne muscular dystrophy (DMD); chronic kidney disease (CKD) D) secondary hyperparathyroidism (HPT) in patients on dialysis with hypercalcemia in patients with primary HPT or parathyroid carcinoma who are advised to undergo parathyroidectomy based on serum calcium levels but cannot undergo parathyroidectomy; hallucinations and delusions due to Parkinson's disease psychosis; schizophrenia; acute manic or mixed episodes associated with bipolar disorder type I; chronic hepatitis C (HC) infection (as a component of a combination antiviral treatment regimen with pegylated interferon alpha and ribavirin for HCV genotype 1 infected subjects with compensated liver disease); Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+BC) (e.g., after treatment failure with letrozole or anastrozole, in combination with exemestane), advanced neuroendocrine tumors of pancreatic origin (PNET), unresectable, locally advanced, or metastatic advanced well-differentiated nonfunctioning neuroendocrine tumors (NET) of gastrointestinal (GI) or pulmonary origin, advanced renal cell carcinoma (RCC) (e.g., after treatment failure with sunitinib or sorafenib), renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, and patients requiring treatment intervention but TSC in patients with subependymal giant cell astrocytoma (SEGA) who are not candidates for surgical resection; type 2 diabetes in adults (as an adjunct to diet and exercise therapy to improve glycemic control); major depressive disorder (MDD); thrombotic cardiovascular events (e.g., cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome (ACS); stroke and systemic embolism in patients with non-valvular atrial fibrillation; deep vein thrombosis (DVT) that may lead to pulmonary embolism (PE) in patients who have undergone hip or knee replacement surgery; DVT, PE; recurrent DVT and PE following initial treatment; and methotrexate. moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or resistance to prior imatinib therapy; acute migraine with or without aura; chronic and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosed patients or patients who are resistant or intolerant to prior imatinib-containing therapy; atrial fibrillation (AF) in patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or are cardioverted; asthma in patients 4 years of age and older; obstructive pulmonary disease and reduced exacerbations in patients with chronic obstructive pulmonary disease; erectile dysfunction (ED);Benign prostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHO classification group 1) (for the purpose of improving exercise capacity), gout flares, familial Mediterranean fever, antiretroviral therapy, anxiety disorder, panic disorder, seizures, insomnia, hypertension, cardiovascular disease, hyperlipidemia, primary renal cancer, advanced primary liver cancer, radioactive iodine-resistant advanced thyroid cancer, cancers such as renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumors, mantle cell lymphoma in patients who have received at least one prior treatment, chronic lymphocytic leukemia / small lymphocytic lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma with deletion of the short arm of chromosome 17, Waldenstrom macroglobulinemia, marginal zone lymphoma in patients who require systemic treatment and have received at least one anti-CD20 treatment, BRAF Unresectable or metastatic melanoma with V600E or V600K mutations, allergy, transplantation, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen, treatment of clinically significant polycythemia and euvolemic hyponatremia, including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of highly emetogenic cancer chemotherapy (HEC) including high doses of cisplatin, prevention of delayed nausea and vomiting associated with initial and repeated courses of moderately emetogenic cancer chemotherapy (MEC), overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, patients whose tumors are epidermal growth factor receptor agonists as detected by an FDA-approved test, metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 (L858R) substitution mutations and receiving first-line treatment, maintenance treatment, or second-line or higher treatment after progression; locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine; HER-2 positive metastatic breast cancer previously treated with trastuzumab and a taxane, either separately or in combination, in patients who have previously been treated for metastatic disease or who have developed disease recurrence during or within 6 months of completing adjuvant therapy; adult Ph+ chronic myeloid leukemia (CML) in chronic, accelerated, or acute phase with resistance or intolerance to previous therapy; gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate; advanced renal cell carcinoma (RCC), unresectable;Locally progressive, or advanced well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with metastatic disease, CCR5-tropic HIV-1 infection in patients 2 years of age or older weighing at least 10 kg in combination with other antiretrovirals, advanced renal cell carcinoma, advanced soft tissue sarcoma who have received previous chemotherapy, manic episodes and mixed episodes associated with bipolar disorder type I, major depressive disorder, hyperirritability associated with autistic disorder, Tourette's disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one prior systemic therapy, inadequately controlled with dapagliflozin. and improving glycemic control in adults with type 2 diabetes mellitus (T2DM) who are currently receiving or already being treated with dapagliflozin and saxagliptin; advanced metastatic medullary thyroid carcinoma (MTC); advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy; chronic, accelerated, or acute phase chronic myeloid leukemia (CML) or Ph+ALL in adults for whom other tyrosine kinase inhibitor (TKI) therapy is not indicated; and adult T315I-positive CML (chronic, accelerated, or acute phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). +ALL), invasive aspergillosis, invasive mucormycosis, and homozygous familial hypercholesterolemia (HoFH), reducing low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apoB), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with schizophrenia in adults, aromatase inhibitors as initial endocrine therapy in postmenopausal women, or in combination with fulvestrant in women with disease progression after endocrine therapy, hormone receptor (HR)-positive, human epithelial cell proliferation inhibitors (HEPs). HER2-negative advanced or metastatic breast cancer, major depressive disorder (MDD), suppression of motor and vocal tics in patients with Tourette's disorder who have not responded adequately to standard treatment, treatment of multiple myeloma in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have shown disease progression within 60 days of completing the last treatment, non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of first-line platinum-based chemotherapy, locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen,Patients with locally advanced, unresectable, or metastatic pancreatic cancer, overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) requiring treatment intervention but not eligible for curative surgical resection, renal angiomyolipoma, tuberous sclerosis complex, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression after endocrine therapy and prior chemotherapy in the metastatic setting. As monotherapy for the treatment of adult patients, in combination with fulvestrant, with HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy, with cystic fibrosis (CF) in patients 2 years of age or older who have one mutation in the CFTR gene that responds to ivacaftor based on clinical and / or in vitro assay data, with germline BRCA-mutated advanced ovarian cancer in adult patients who have been treated with three or more prior lines of chemotherapy and who are suspected of having adverse or suspected adverse outcomes, with primary myelofibrosis, post-polycythemia vera myelofibrosis, and with this patients with intermediate or high risk myelofibrosis, including post-alterative thrombocythemia myelofibrosis; patients with polycythemia vera who have had an inadequate response to or are intolerant to hydroxyurea; patients with schizophrenia as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD); patients with at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene who are homozygous for the F508del mutation or who respond to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence; Cystic fibrosis (CF) in patients aged 12 years and older with metastatic colorectal cancer (CRC) previously treated with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy; locally advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) patients previously treated with imatinib mesylate and sunitinib malate; hepatocellular carcinoma (HCC) previously treated with sorafenib; chronic HCV genotype 1 or 3 infection with sofosbuvir, with or without ribavirin;The tumor expresses anaplastic lymphoma kinase (AKI), as detected by an FDA-approved test. metastatic non-small cell lung cancer (NSCLC) in patients whose cancer is BRAF (LK) or ROS1 positive; opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to a previous cancer or its treatment and who do not require frequent (e.g., weekly) opioid dose escalation; unresectable or metastatic melanoma in patients with a BRAF V600E mutation as detected by an FDA-approved test; treatment of unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation as detected by an FDA-approved test in combination with trametinib; melanoma in patients with a BRAF V600E or V600K mutation as detected by an FDA-approved test and lymph node metastasis after complete resection; metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation as detected by an FDA-approved test; and treatment of BRAF V600E for which there are no satisfactory local treatment options. treatment of locally advanced or metastatic anaplastic thyroid carcinoma (ATC) in patients with a V600E mutation; treatment of chronic HCV genotype 1 or 4 infection in adults with or without ribavirin; treatment of patients with non-metastatic castration-resistant prostate cancer; treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib; treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older; treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies; treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; BRAF as detected by an FDA-approved test. Treatment in combination with binimetinib in patients with unresectable or metastatic melanoma with V600E or V600K mutations, coexisting medical or psychiatric conditions causing significant distress or interpersonal difficulties; interpersonal problems;or treatment of premenopausal women with acquired generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire not due to the effects of drugs or other medicinal substances; reducing the risk of hospitalization due to worsening heart failure in patients with stable symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less, with a resting heart rate of 70 beats per minute or greater in sinus rhythm, who are taking a maximally tolerated dose of a beta-blocker, or for whom beta-blocker use is contraindicated; treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; treatment of patients with multiple myeloma who have received at least two prior regimens containing bortezomib and an immunomodulatory agent; treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy, or who are not candidates for surgery or radiation therapy; treatment of patients with unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; 21. The use according to any one of claims 1 to 20, wherein the compound is used to treat a disease or condition selected from the group consisting of: treatment of patients with Erdheim-Chester disease with a V600 mutation;

22. The patient is selected from the group consisting of: non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age or older; relapsed follicular lymphoma (FL) in adults who have received at least two prior systemic therapies; adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies in combination with binimetinib; and BRAF as detected by an FDA-approved test. Treatment of premenopausal women with unresectable or metastatic melanoma with V600E or V600K mutations, acquired generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is causing significant distress or interpersonal difficulties and is not due to a coexisting medical or psychiatric condition; relationship problems; or the effects of drugs or other medicinal substances, and a resting heart rate of 70 beats per minute or greater Reducing the risk of hospitalization due to worsening heart failure in patients with stable, symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less who are in sinus rhythm and taking a maximum tolerated dose of a beta-blocker or who have a contraindication to beta-blocker use; adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent; adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy or who are not candidates for surgery or radiation therapy; unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; Erdheim-Chester disease with a V600 mutation; non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that has progressed on or is intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older; adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies; adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies; adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies; BRAF as detected by an FDA-approved test. Treatment in combination with binimetinib in patients with unresectable or metastatic melanoma with V600E or V600K mutations; premenopausal women with acquired generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is not due to a coexisting medical or psychiatric condition causing significant distress or interpersonal difficulties; relationship problems; or the effects of drugs or other medicinal substances; reducing the risk of hospitalization due to worsening heart failure in patients with stable symptomatic chronic heart failure with a left ventricular ejection fraction of 35% or less, who have a resting heart rate of 70 beats per minute or more, are taking a maximally tolerated dose of a beta-blocker, or who have a contraindication to beta-blocker use, and are in sinus rhythm;21. The use of any one of claims 1 or 4-20, wherein the patient is treated for a disease or condition selected from the group consisting of: adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test; patients with multiple myeloma who have received at least two prior regimens comprising bortezomib and an immunomodulatory agent, adult patients with locally advanced basal cell carcinoma (BCC) that has relapsed after surgery or radiation therapy, or adult patients who are not candidates for surgery or radiation therapy; patients with unresectable or metastatic melanoma with a BRAF V600E mutation as detected by an FDA-approved test; and treatment of patients with Erdheim-Chester disease with a BRAF V600E mutation.

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