Treatment method with CYP3A4 substrate drugs

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 on July 16, 2018, which is hereby incorporated by reference in its entirety.

[0002]

[0002] Posaconazole, also known as Noxafil and Posanol, is indicated for use in patients at high risk of 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 with prolonged chemotherapy - induced neutropenia, to prevent the above - mentioned infections, and to treat oropharyngeal candidiasis (OPC) including refractory oropharyngeal candidiasis (rOPC) to itraconazole and / or fluconazole, invasive aspergillosis, and zygomycosis. Posaconazole is used "off - label" for the treatment of allergic bronchopulmonary aspergillosis, prevention and treatment of recurrent esophageal candidiasis following HIV infection, fusarium infections, and chronic or cavitary necrotizing pulmonary aspergillosis.

[0003]

[0003] Posaconazole is a potent inhibitor of the CYP3A4 enzyme, which belongs to the cytochrome P450 family of oxidase enzymes present in the liver. Such cytochrome P450 enzymes, such as CYP3A4, oxidize organic small molecules in the body, such as toxins and certain drugs, to inactivate and / or degrade them. Organic molecules in the body (such as drugs) that are mainly oxidized by specific enzymes are referred to as "substrates" of the relevant enzymes. That is, drugs that are mainly oxidized by the CYP3A4 enzyme are "CYP3A4 substrate drugs".

[0004]

[0004] The label of Noxafil specifically prohibits co-administration with certain drugs metabolized by CYP3A4 such as sirolimus, CYP3A4 substrates such as pimozide and quinidine, HMG-CoA reductase inhibitors mainly metabolized via CYP3A4, ergot alkaloids, and with CYP3A4 substrate drugs. Also, when co-administering posaconazole with other drugs metabolized by CYP3A4, including tacrolimus, cyclosporine, vinca alkaloids such as vincristine and vinblastine, and calcium antagonists such as verapamil, diltiazem, nifedipine, nicardipine, and felodipine, dose adjustment needs to be considered. However, while the label of Noxafil identifies specific drug interactions associated with the co-administration of posaconazole and CYP3A4 substrate drugs, it does not indicate anything regarding the administration of CYP3A4 substrate drugs after discontinuation of posaconazole.

Summary of the Invention

Problems to be Solved by the Invention

[0005]

[0005] The inventor of the present invention has found that in order to prevent or reduce the occurrence of dangerous side effects caused by CYP3A4 substrate drugs, after discontinuation of posaconazole, it is necessary to delay the administration of CYP3A4 substrate drugs or, in some cases, adjust the dose of CYP3A4 substrate drugs at specified time intervals.

Means for Solving the Problems

[0006]

[0006] The present disclosure provides a method of treating a patient who has been pre-administered posaconazole with a therapeutically effective regimen prior with a CYP3A4 substrate drug for which co-administration with a potent CYP3A4 inhibitor is prohibited.

[0007]

[0007] The applicant has discovered that although most CYP3A4 substrate drugs are only prohibited from co - administration with strong CYP3A4 inhibitors such as posaconazole, when a CYP3A4 substrate drug is administered to a patient immediately after discontinuation of posaconazole treatment, safety cannot be guaranteed. Furthermore, the applicant has found that when posaconazole accumulates in the body of a patient, especially in the specific patient population described in this specification, if the administration of a CYP3A4 substrate drug is too early after discontinuation of the posaconazole regimen, it may cause serious and life - threatening side effects. Therefore, for CYP3A4 substrate drugs that are prohibited from co - administration with CYP3A4 substrate drugs, especially strong CYP3A4 inhibitors (including but not limited to posaconazole), a wash - out period or deferral period of about 2 to 42 days (for example, about 2 to 21 days) should be set between the discontinuation of posaconazole administration and the start of CYP3A4 substrate drug administration to avoid or reduce the occurrence of side effects caused by the administration of CYP3A4 substrate drugs. Alternatively, according to the applicant, in some embodiments, instead of deferring the administration of a CYP3A4 substrate drug after discontinuation of posaconazole administration, after discontinuation of the posaconazole regimen, for a certain period (about 2 to 42 days (for example, about 2 to 21 days)), the dose of the CYP3A4 substrate drug is reduced (reduced from the recommended dose of the CYP3A4 substrate drug) and then administered, and then the dose of the CYP3A4 substrate drug is increased to the recommended level, the safety of the patients administered can be guaranteed.

[0008]

[0008] In certain embodiments, the methods of the present disclosure that delay treatment with a CYP3A4 substrate drug for about 2 to 42 days (e.g., about 2 to 21 days) or reduce the dose of a CYP3A4 substrate drug after posaconazole administration cessation are directed to normal patients, e.g., non-obese CYP3A4 normal metabolizers. In certain embodiments, the methods of the present disclosure that delay treatment with a CYP3A4 substrate drug for about 2 to 42 days (e.g., about 2 to 21 days) or reduce the dose of a CYP3A4 substrate drug after posaconazole administration cessation are directed to patients having certain physiological characteristics described herein. Since patients may be exposed to a greater amount of CYP3A4 substrate drug than is well known after posaconazole administration cessation, in order to avoid or reduce the occurrence of side effects associated with treatment with a CYP3A4 substrate drug, it is necessary to set a longer "drug holiday" period prior to the initiation of treatment with a CYP3A4 substrate drug after posaconazole administration cessation or to extend the treatment with a reduced dose of a CYP3A4 substrate drug for a longer period. More specifically, according to the applicants' findings, patients having certain physiological characteristics will be unexpectedly exposed to a greater amount of the administered CYP3A4 substrate drug after posaconazole administration cessation compared to "normal" patients (e.g., patients who are otherwise the same but do not have the certain physiological characteristics described herein). For example, patients with a BMI value in the "normal" range (about 18.5 to 24.9) may have a significant decrease in the excretion of CYP3A4 substrate drugs, and such patients are referred to as CYP3A4 poor metabolizers or CYP3A4 intermediate metabolizers. Thus, as described herein, according to the inventors' findings of the present invention, for certain patient populations, it may be necessary to set a longer drug holiday period from posaconazole administration cessation to the start of treatment with a CYP3A4 substrate drug, or to reduce the dose of a CYP3A4 substrate drug for a certain period after posaconazole treatment cessation and then conduct the treatment.

[0009]

[0009] In various embodiments, the present disclosure provides a method of treating a patient who delays the first treatment with a CYP3A4 substrate drug until about 2 to 42 days (e.g., 2 to 21 days) have elapsed since discontinuation of posaconazole administration. In an embodiment, the CYP3A4 substrate drug is a drug that is contraindicated for combination use with a strong CYP3A4 inhibitor, such as, but not limited to, posaconazole. Thus, in various embodiments, the present disclosure provides a method of treating a patient who has previously received multiple doses of posaconazole with a CYP3A4 substrate drug that is contraindicated for combination treatment with a strong CYP3A4 inhibitor, the method comprising administering, or prescribing to initiate, the first treatment to the patient with a fixed dose of the CYP3A4 substrate drug at least 2 to 42 days (e.g., 2 to 21 days) after discontinuation of posaconazole treatment.

[0010]

[0010] In various embodiments, the present disclosure provides a method of administering, or prescribing to initiate, the first treatment to a patient with a CYP3A4 substrate drug at a dose of about 50% or less of the reference dose of the CYP3A4 substrate drug for about 2 to 42 days (e.g., 2 to 21 days) after discontinuation of posaconazole treatment. Thus, in various embodiments, the method comprises administering, or prescribing to initiate, treatment to a patient in need thereof with a therapeutically effective amount of a CYP3A4 substrate drug that is contraindicated for combination 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 reference dose for about 2 to 42 days (e.g., 2 to 21 days) after interruption of the posaconazole regimen.

[0011]

[0011] In some embodiments, after a delay as described herein (e.g., at least 2 days, including 242 days), once the CYP3A substrate drug is safe, the CYP3A4 substrate drug is administered immediately. In some embodiments, the CYP3A4 substrate drug is administered in step (d) once at least one of the AUC, Cmax, GMR AUC, or GMR Cmax of the CYP3A4 substrate drug does not exceed the maximum level at which the benefit of treating the patient outweighs the risk of high exposure to the CYP3A4 substrate drug. In some embodiments, the maximum level at which the benefit of treating the patient outweighs the risk of high exposure to the CYP3A4 substrate drug is the target safety level described 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 exceeds the baseline but does not exceed the target safety level described 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 on 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 on the day the CYP3A4 substrate drug is administered, but does not exceed the target safety level described in Table A for the CYP3A4 substrate drug. 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 times 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 times the predicted AUC or Cmax, but does not exceed the target safety level described in Table A for the CYP3A4 substrate drug.

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

[0013] In one embodiment, the method is for non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that is progressing on or intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Doose syndrome in patients 2 years of age and 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 treatments; 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 detected by an FDA-approved test, significant pain or interpersonal relationship difficulties, coexisting medical or mental conditions; interpersonal relationship problems; or acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is not due to the effects of drugs or other pharmaceutical substances in premenopausal women; 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, in sinus rhythm with a resting heart rate of 70 beats per minute or more, taking the maximum tolerated dose of a beta blocker, or in whom the use of a beta blocker is contraindicated; adult patients with relapsed or refractory acute myeloid leukemia (AML) with a sensitive IDH1 mutation detected by an FDA-approved test; multiple myeloma that has received at least two prior regimens including bortezomib and immunomodulatory agents; adult patients with locally advanced basal cell carcinoma (BCC) that has recurred after surgery or radiation therapy, or adult patients who are not candidates for surgery or radiation therapy; unresectable or metastatic melanoma with a BRAF V600E mutation detected by an FDA-approved test; Erdheim-Chester disease with a BRAF V600 mutation; non-metastatic castration-resistant prostate cancer; anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) that is progressing on or intolerant to crizotinib; seizures associated with Lennox-Gastaut syndrome or Doose syndrome in patients 2 years of age and older;Treatment of patients having a disease or condition selected from the group consisting of: 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 treatments; adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic treatments; treatment in combination with binimetinib of patients having unresectable or metastatic melanoma with a BRAF V600E or V600K mutation detected by an FDA-approved test; acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is not due to coexisting medical or psychiatric conditions; problems in personal relationships; or the effects of drugs or other pharmaceutical substances, in premenopausal women; 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, in sinus rhythm with a resting heart rate of 70 beats per minute or more, who are taking the maximum tolerated dose of a beta blocker or for whom beta blocker use is contraindicated; adult patients with relapsed or refractory acute myeloid leukemia (AML) with a sensitive IDH1 mutation detected by an FDA-approved test; patients with multiple myeloma who have received at least two prior regimens, including bortezomib and immunomodulatory agents; treatment of adult patients having locally advanced basal cell carcinoma (BCC) that has recurred after surgery or radiation therapy, or adult patients not eligible for surgery or radiation therapy; patients having unresectable or metastatic melanoma with a BRAF V600E mutation detected by an FDA-approved test; and treatment of patients having Erdheim-Chester disease with a BRAF V600 mutation.;

[0014]

[0014] In various embodiments, the present disclosure relates to schizophrenia in adults and adolescents (13 - 17 years old), depressive episodes associated with type I bipolar disorder (bipolar depression) in adults and pediatric patients (10 - 17 years old) (as monotherapy or as adjunctive therapy with lithium or valproic acid), 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 and older who are homozygous for the F508del mutation in the CFTR gene, chronic lymphocytic leukemia in patients with a deletion of the short arm of chromosome 17 who have received at least one pretreatment, unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have previously received a regimen containing anthracyclines, progressive or metastatic breast cancer in postmenopausal women with hormone receptor (HR) positivity, progressive or metastatic breast cancer negative for human epidermal growth factor receptor 2 (HER2), negative progressive or metastatic breast cancer (in combination with an aromatase inhibitor for postmenopausal women), Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT) in dialysis patients with chronic kidney disease (CKD), hypercalcemia in patients with primary hyperparathyroidism or parathyroid cancer who are recommended parathyroidectomy based on serum calcium levels but are unable to undergo parathyroidectomy, hallucinations and delusions due to Parkinson's disease psychosis, schizophrenia, acute manic or mixed episodes associated with type I bipolar disorder, chronic hepatitis C (CHC) infection (as a component of a combination antiviral treatment regimen using peginterferon alpha and ribavirin for HCV genotype 1 - infected subjects with compensated liver disease), progressive hormone receptor - positive, HER2 - negative breast cancer (progressive HR+BC) in postmenopausal women (e.g., in combination with exemestane after treatment failure with letrozole or anastrozole), progressive neuroendocrine tumors (PNET) of pancreatic origin, unresectable, locally progressive or metastatic progressive well - differentiated non - functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, progressive renal cell carcinoma (RCC) (e.g., after treatment failure with sunitinib or sorafenib), renal angiomyolipoma and tuberous sclerosis complex (TSC) that do not require immediate surgery, TSC in patients with subependymal giant cell astrocytoma (SEGA) who require treatment intervention but are not candidates for surgical resection.Type 2 diabetes in adults (as an adjunct to diet and exercise therapy for improving blood glucose control), major depressive disorder (MDD), thrombotic cardiovascular events (such as 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 induce pulmonary embolism (PE) in patients who have undergone hip or knee joint replacement surgery, DVT, PE, recurrent DVT and PE associated with initial treatment, moderate to severe active rheumatoid arthritis in patients showing inadequate response or resistance to methotrexate, acute migraine with or without aura, chronic phase and accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in newly diagnosed patients or patients showing resistance or intolerance to prior treatment including imatinib, atrial fibrillation (AF) in patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or have been defibrillated, asthma in patients 4 years of age and older, obstructive lung and exacerbation reduction in patients with chronic obstructive pulmonary disease, erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHO group 1) (for the purpose of improving exercise capacity), gouty erythema, familial Mediterranean fever, antiretroviral therapy, anxiety disorder, panic disorder, seizures, insomnia, hypertension, cardiovascular disease, hyperlipidemia, primary renal cancer, progressive primary liver cancer, radioiodine-resistant progressive 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, Waldenström macroglobulinemia, marginal zone lymphoma in patients who require systemic treatment and have been treated with at least one anti-CD20-based treatment, unresectable or metastatic melanoma with BRAF V600E or V600K mutation, allergy, transplantation, hormone-refractory metastatic prostate cancer treated with a treatment regimen previously containing docetaxel, hormone-refractory metastatic prostate cancer treated with a treatment regimen previously containing docetaxel, clinical significant polycythemia and normovolemic hyponatremia treatment including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) containing high doses of cisplatin, prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC), overactive bladder with symptoms of urge incontinence, urgency, and frequency, metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations detected by FDA-approved tests, and receiving first-line, maintenance, or second-line or greater treatment after progression, locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine, in patients who have received prior treatment for metastatic disease or have developed disease recurrence within 6 months of completion of adjuvant therapy, HER-2 positive metastatic breast cancer previously treated with trastuzumab and taxanes separately or in combination, adult patients with chronic phase, accelerated phase, or acute phase Philadelphia chromosome-positive chronic myeloid leukemia (CML) with resistance or intolerance to prior treatment, 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-directed HIV-1 infection in patients 2 years of age and older weighing at least 10 kg in combination with other antiretroviral drugs, advanced renal cell carcinoma, advanced soft tissue sarcoma previously treated with chemotherapy, manic and mixed episodes associated with type I bipolar disorder, major depressive disorder, hypersensitivity associated with autistic disorder, Tourette disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one prior systemic therapy, improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM) with inadequate control by dapagliflozin or already treated with dapagliflozin and saxagliptin, advanced metastatic medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC) previously treated with anti-angiogenic therapy, chronic phase, accelerated phase, or acute phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in adults not eligible for other tyrosine kinase inhibitor (TKI) therapies, adult patients with T315I-positive CML (chronic phase, accelerated phase, or acute phase) or T315I-positive Philadelphia chromosome,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 positive acute lymphoblastic leukemia (Ph+ALL), invasive aspergillosis, invasive mucormycosis, homozygous familial hypercholesterolemia (HoFH); adult schizophrenia; anastrozole as initial endocrine therapy in postmenopausal women; or fulvestrant in combination with endocrine therapy in women with disease progression after endocrine therapy, for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer; major depressive disorder (MDD); suppressing motor and vocal tics in patients with Tourette disorder who have not responded adequately to standard treatment; treating multiple myeloma in patients who have received at least two previous treatments including lenalidomide and a proteasome inhibitor and have shown disease progression within 60 days of completion of the last treatment; non-small cell lung cancer (NSCLC) that has not progressed after 4 cycles of platinum-based first-line chemotherapy; locally advanced or metastatic NSCLC after failure of at least one previous chemotherapy regimen; locally advanced, unresectable or metastatic pancreatic cancer; urge incontinence; overactive bladder with symptoms of urgency and frequency; progressive renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib; subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) that requires treatment intervention but is not a candidate for therapeutic surgical resection, renal angiomyolipoma, tuberous sclerosis complex; 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 previous chemotherapy in the metastatic setting, in combination with fulvestrant, for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy; cystic fibrosis (CF) in patients 2 years of age and older with one mutation in the CFTR gene responsive to ivacaftor, based on clinical and / or in vitro assay data; germline BRCA-mutated advanced ovarian cancer in adult patients who have been treated in 3 or more previous chemotherapy lines and who have deleterious or suspected deleterious mutations; primary myelofibrosis,Intermediate- or high-risk myelofibrosis, including post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis, in patients with polycythemia vera who have shown an inadequate response to hydroxyurea or are intolerant to hydroxyurea; as adjuvant therapy to antidepressants for the treatment of major depressive disorder (MDD); in patients 12 years of age and older with cystic fibrosis (CF) who are homozygous for the F508del mutation 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; metastatic colorectal cancer (CRC) patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, in the case of 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 or without ribavirin and sofosbuvir; metastatic non-small cell lung cancer (NSCLC) in patients whose tumors are positive for anaplastic lymphoma kinase (ALK) or ROS1 as detected by an FDA-approved test; opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including those 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 detected by an FDA-approved test; treatment in combination with trametinib for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation detected by an FDA-approved test; melanoma in patients with a BRAF V600E or V600K mutation 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 detected by an FDA-approved test; locally advanced or metastatic anaplastic thyroid cancer (ATC) in patients with a BRAF V600E mutation who have no satisfactory local treatment optionsTreatment 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 are progressing on or intolerant to crizotinib, treatment of seizures associated with Lennox-Gastaut syndrome or Doose syndrome in patients 2 years of age and older, having 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 treatments, treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic treatments, treatment in combination with vemurafenib of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations detected by an FDA-approved test, treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is not due to coexisting medical or psychiatric conditions; relationship problems; or the effects of drugs or other pharmaceutical 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, in sinus rhythm with a resting heart rate of 70 beats per minute or more, taking the maximum 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 sensitive IDH1 mutations detected by an FDA-approved test, treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and immunomodulatory agents, treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred after surgery or radiation therapy, or adult patients who are not candidates for surgery or radiation therapy, treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutations detected by an FDA-approved test, and treatment of patients with Erdheim-Chester disease with BRAF V600 mutations, a method of treating a patient having a disease or condition selected from the group consisting of, or a method of prescribing treatment to a patient.

[0015]

[0015] In some embodiments, the method comprises treating a disease or condition with a CYP3A4 substrate drug for which co - administration with a strong CYP3A4 inhibitor is prohibited, where the patient needs to be treated with a strong CYP3A4 inhibitor (i.e., posaconazole). In some embodiments, the method comprises (a) delaying the initial treatment with the CYP3A4 substrate drug for at least about 2 to 42 days after discontinuation of posaconazole administration, and then (b) administering or prescribing treatment with the CYP3A4 substrate drug. In other embodiments, the method comprises (a) delaying the initial treatment with the CYP3A4 substrate drug for at least about 2 to 21 days from the discontinuation of the posaconazole regimen, and then (b) administering or prescribing treatment with the CYP3A4 substrate drug at a dose of about 50% or less of the reference dose for at least about 2 to 42 days from the discontinuation of posaconazole administration.

Brief Description of the Drawings

[0016] Brief Description of the Drawings

Figure 1

[0016] Shows the mean (± standard error) plasma posaconazole concentrations in normal - weight subjects and in obese subjects during and after discontinuation of posaconazole administration. See Table 2 for the pharmacokinetic analysis.

Figure 2A

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

Figure 2B

Figure 2C

Figure 2D

Figure 3

[0018] Shows the arithmetic mean (± standard error) ratio of the lurasidone AUC during and after posaconazole administration, divided by the AUC in the baseline control state in the normal weight and obese subject groups. At all time points, the ratio was significantly different from 1.0.

Figure 4

[0019] Shows the relationship between plasma posaconazole concentration (X-axis) and lurasidone AUC (Y-axis). The solid line represents the optimal function determined by linear regression analysis. The fitted function is Y = 2.38X0.58 + 110.6.

Figure 5

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

Figure 6A

[0021] Shows the mean (± SD) plasma ranolazine concentrations in normal weight subjects (Figure 6A) at baseline (day 1), during posaconazole co-administration (day 15), and after posaconazole discontinuation (days 18 - 29). See Table 10 for the pharmacokinetic analysis. The upper panel is on a linear concentration axis. The lower panel is on a logarithmic concentration axis.

Figure 6B

Figure 7

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

Figure 8

[0023] The actual lurasidone AUC ratios (dashed line) measured in normal weight and obese subjects are shown, compared to the predicted 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 ratios (dashed line) measured in normal weight and obese subjects are shown, compared to the predicted ranolazine AUC in patients that could be predicted from the posaconazole half-life (predicted ranolazine AUC ratio, solid line).

Figure 10

[0025] The predicted decay curve of encorafenib (solid line), and the maximum (the "target safety level") GMR of the AUC levels achieved by the methods disclosed herein are shown.

DETAILED DESCRIPTION OF THE INVENTION

[0017]

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

[0018]

[0027] As used herein, "about" refers to an amount that is somewhat more or less than the specified reference value, e.g., ±5 to 10% of the indicator modified by "about", or the range that can be inferred by one of ordinary skill in the art from the context (e.g., about 50% of the median value). "About" also includes the reference value. For example, if the BMI is about 40, values around 40 are included.

[0019]

[0028] As used herein, "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 pediatric patient.

[0020]

[0029] As used herein, "treatment" or "therapy" refers to the overall treatment regimen of a CYP3A4 substrate drug when used in combination with a CYP3A4 substrate drug during the period of 2 to 42 days after discontinuation of posaconazole treatment. For example, during this period, the patient will be prescribed or administered (including self-administration) a CYP3A4 substrate drug at a reduced dose (e.g., about 50% or less of the reference dose of the CYP3A4 substrate drug). In some embodiments, the patient is not administered a CYP3A4 substrate drug for 2 to 42 days, or is advised not to take the CYP3A4 substrate drug in the dosage regimen prescribed by the doctor, and thereafter, for example, can resume (or be so prescribed) taking the CYP3A4 substrate drug at the reference amount.

[0021]

[0030] As used herein, "treatment" and "treating" refer to (i) an act of preventing the occurrence of a disease or disorder in a subject who may have a predisposition to a particular disease or disorder but has not yet been diagnosed as having the disease or disorder, (ii) an act of curing, treating, or suppressing a disease, i.e., an act of preventing its onset, or (iii) an act of improving a disease by reducing or eliminating symptoms and / or signs and / or regression of the disease. In some embodiments, "treatment" and "treating" include administering by a therapeutically effective regimen as defined herein.

[0022]

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

[0023]

[0032] As used herein, "patient" refers to a human subject having signs that can be improved by posaconazole treatment and in need of treatment with a CYP3A4 substrate drug. For example, prior to receiving posaconazole treatment or prescription, a patient has both a first sign that can be improved by posaconazole treatment and a second sign that can be improved by CYP3A4 substrate drug treatment. In some embodiments, a patient is first treated with posaconazole, then the posaconazole regimen is discontinued, and switched to the treatment described herein with a CYP3A4 substrate drug. In other embodiments, a patient develops a sign that can be improved by CYP3A4 substrate drug treatment during posaconazole treatment. In some embodiments, a patient discontinues the posaconazole regimen and switches to the treatment described herein with a CYP3A4 substrate drug. As used herein, "patient" does not include a subject who develops a sign that can be improved by CYP3A4 substrate drug treatment at some point after discontinuing posaconazole treatment.

[0024]

[0033] As used herein, "a patient treated with posaconazole" or "a patient who has previously taken posaconazole" refers to a patient having signs that have been improved by posaconazole treatment.

[0025]

[0034] As used herein, "normal baseline C max " or "baseline C max " refers to the average C max of a drug measured when the same dose is administered to a population of patients who have not been previously treated with a strong CYP3A4 inhibitor (e.g., posaconazole) under otherwise identical conditions. For example, when the CYP3A4 substrate drug is ranolazine, the "normal baseline C max " of ranolazine is the average C max of ranolazine measured when the same dose of ranolazine is administered to a population of patients who have not been previously treated with a strong CYP3A4 inhibitor (e.g., posaconazole) under otherwise identical conditions. As another example, when the CYP3A4 substrate drug is lurasidone, the "normal baseline C max」 is the mean C of lurasidone measured when the same dose of lurasidone is administered to patients who have not been previously treated with a strong CYP3A4 inhibitor (e.g., posaconazole) while other conditions are the same. max As another example, when the CYP3A4 substrate drug is tadalafil, the "usual baseline C max 」 is the mean C of tadalafil measured when the same dose of tadalafil is administered to patients who have not been previously treated with a strong CYP3A4 inhibitor (e.g., posaconazole) while other conditions are the same. max is.

[0026]

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

[0027]

[0036] As used herein, "normal," "reference," and their derivatives and variations refer to a non-obese state in a human having at least one of the characteristics of a BMI of less than about 35, an ideal body weight ratio (%IBW) of less than about 150%, a waist size of less than about 42 inches, a body fat percentage of less than about 40%, an android body fat percentage of less than about 40%, a gynoid body fat percentage of less than about 40%, and a total body fat of less than about 40 kg. Unless otherwise defined, "normal metabolizer" further means a CYP3A4 normal metabolizer.

[0028]

[0037] As used herein, "reference dose" refers to the dose of a specific CYP3A4 substrate drug described in the label of a manufacturer approved by the FDA (e.g., the most recently FDA-approved label for a specific CYP3A4 drug effective as of November 14, 2018), and is prescribed to a patient who has not been previously treated with a potent CYP3A4 inhibitor (e.g., posaconazole), with other conditions being the same. It is common for a specific drug to be approved for multiple different indications, and each indication may have a different reference dose. Similarly, drugs are generally 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. Further, in some drug labels, a range of doses may be recommended for treating a specific indication, but for an individual patient, a specific dose within the recommended range is safe and therapeutically effective. In such embodiments, the dose that is safe and therapeutically effective for a specific patient is the "reference dose" for that patient. Specific reference doses for CYP3A4 substrate drugs are provided herein.

[0029]

[0038] Any reference in this specification to a CYP3A4 substrate drug also includes all pharmaceutically acceptable isomers (e.g., stereoisomers), solvates, hydrates, polymorphs, salts, and prodrugs (e.g., esters and phosphates) thereof. For example, a reference in this specification to solifenacin includes its pharmaceutically acceptable salts such as succinate. As another example, a reference in this specification to naloxegol includes its pharmaceutically acceptable salts such as oxalate. As another example, a reference in this specification to aripiprazole 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 enantiomers (enantiomers), mixtures of enantiomers (racemates, racemic mixtures), geometric (cis / trans or E / Z) isomers, and isomers of compounds having multiple chiral centers that are not mirror images of each other (diastereoisomers). The CYP3A4 substrate drugs of the present invention may occur as racemates, racemic mixtures, individual diastereoisomers, or enantiomers, or may exist as geometric isomers, and all isomers of said compounds are included in the present invention. Further, the CYP3A4 substrate drug may include any ratio for a mixture of stereoisomers, for example, 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, etc., from about 1:99 to about 99:1 (including all ratios and subranges therebetween).

[0031]

[0040] This disclosure also includes combinations of CYP3A4 substrate drugs described herein. Thus, in accordance with any of the embodiments of this disclosure, a patient may be treated with multiple CYP3A4 substrate drugs such as lurasidone and ranolazine.

[0032]

[0041] This specification discloses a method of treating or prescribing treatment for a patient with a CYP3A4 substrate drug that is contraindicated for co-administration with a potent CYP3A4 inhibitor, particularly when a patient who has previously received posaconazole treatment, and in particular a patient having one or more of the physiological characteristics described herein, is subsequently treated with a CYP3A4 substrate drug. That is, the present disclosure provides a method of treating a patient with a CYP3A4 substrate drug that is contraindicated for co-administration with a potent CYP3A4 inhibitor after discontinuing posaconazole treatment for different patient populations (e.g., "normal" patients, obese patients, and / or intermediate or lower CYP3A4 metabolizers (e.g., poor metabolizers)). This specification further describes a method of initiating treatment with a CYP3A4 substrate drug for the treatment of various symptoms and diseases in patients who have previously been treated with posaconazole. The present disclosure also provides a method of preventing or reducing the risk of side effects associated with excessive exposure to a CYP3A4 substrate drug (including methods of treating the symptoms described herein) for patients who are normal, obese, and / or have CYP3A4 dysfunction (e.g., CYP3A4 poor metabolizers or CYP3A4 intermediate metabolizers) and who have received a posaconazole regimen prior to treatment or prescription of a CYP3A4 substrate drug.

[0033]

[0042] In various embodiments, the present disclosure provides a method of treating or prescribing treatment with a CYP3A4 substrate drug to a patient who has been treated with a therapeutically effective regimen comprising posaconazole, after a "drug holiday" period of about 2 to 42 days has elapsed since discontinuation of posaconazole administration. By instituting a drug holiday period, the plasma concentration of posaconazole is reduced to an appropriate level, after which the CYP3A4 substrate drug can be administered without increasing the risk of severe side effects due to the CYP3A4 substrate drug. As described herein, the applicants of the present invention have found that, for patients who have previously received posaconazole treatment, by instituting a "drug holiday" period of about 2 to 42 days from the time of discontinuation of posaconazole treatment in the patient and performing or prescribing the first treatment with a CYP3A4 substrate drug (i.e., starting treatment with a CYP3A4 substrate drug), the CYP3A4 substrate drug can be safely administered. However, since CYP3A4 substrate drugs are usually prohibited from being co-administered with posaconazole, the need for such a drug holiday period has not been known heretofore. Also, as described herein, in some embodiments, instead of instituting a drug holiday period, the applicants of the present invention have found that it may be potentially safe to administer a CYP3A4 substrate drug at a dose of about 50% or less of the reference dose of the CYP3A4 substrate drug to a patient who has previously received posaconazole treatment for about 2 to 42 days from the time of discontinuation of posaconazole treatment in the patient. Similarly, such an administration regimen has not been known heretofore.

[0034]

[0043] Cytochrome P450 3A4 (CYP3A4) is an enzyme that modifies organic small molecules such as certain drugs (especially drugs including the "CYP3A4 substrate drugs" described herein). Thereby, the molecules are metabolized and removed from the human body. Some substances, so-called "CYP3A4 inhibitors", can increase the patient's exposure to CYP3A4 substrate drugs because they reduce the activity of the CYP3A4 enzyme. On the other hand, a potent CYP3A4 inhibitor, when administered at an appropriate dose, can inactivate CYP3A4 and excessively increase the plasma levels of co-administered CYP3A4 substrate drugs, potentially leading to a dangerous situation. Therefore, co-administration of CYP3A4 substrate drugs and potent CYP3A4 inhibitors is prohibited.

[0035]

[0044] As used herein, "potent CYP3A4 inhibitor" refers to a drug 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 using a CYP3A4 substrate drug that is prohibited from co-administration with any of the potent CYP3A4 inhibitors in patients treated with a potent CYP3A4 inhibitor, such as posaconazole.

[0036]

[0045] Co-administration of posaconazole and CYP3A4 substrate drugs is prohibited because it is known to prolong the QT c interval. Clinically significant plasma levels associated with posaconazole and CYP3A4 substrate drugs can significantly increase the levels of CYP3A4 substrate drugs that pose a risk of QT prolongation. The consequences that QT prolongation can bring include arrhythmia, tachycardia, cardiac arrhythmia, palpitations, dizziness, fainting, sudden loss of consciousness, seizures, torsades de pointes, and cardiac death.

[0037]

[0046] For example, according to the drug label of posaconazole (label of NOXAFIL (registered trademark), revised in September 2016), patients are advised to avoid co - administration of posaconazole with specific CYP3A4 substrate drugs such as sirolimus, pimozide, quinidine, HMG - CoA reductase inhibitors, ergot alkaloids, or drugs known to prolong the QT c interval and cause cases of TdP. The label of NOXAFIL (registered trademark) further warns that when co - administering posaconazole with other drugs metabolized by CYP3A4, such as tacrolimus, cyclosporine, vinca alkaloids, and calcium antagonists, dose adjustment should be considered. However, the drug label of posaconazole does not mention anything about the need for a wash - out period setting or population stratification for patients between stopping the administration of posaconazole and starting the administration of CYP3A4 substrates at all.

[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 injection (18 mg / mL), and a delayed - release tablet (100 mg). According to the drug label (Merck), the current recommended dose for invasive aspergillosis and candidiasis infections is 300 mg twice a day on the first day and then 300 mg once a day for intravenous injection or delayed - release tablets, and 200 mg three times a day for oral suspension. The current recommended dose for the treatment of oropharyngeal candidiasis is 100 mg twice a day on the first day and then 100 mg once a day for the next 13 days for oral suspension. The current recommended dose for the treatment of oropharyngeal candidiasis refractory to itraconazole and / or fluconazole is 400 mg twice a day on the first day for oral suspension.

[0039]

[0048] In some embodiments, posaconazole can be adapted for the treatment of fungal infections. In one embodiment, posaconazole can be adapted for the treatment of infections caused by Candida, such as oropharyngeal candidiasis. In one embodiment, posaconazole can be adapted for the treatment of oropharyngeal candidiasis refractory to itraconazole and / or fluconazole. In one embodiment, posaconazole can be adapted for the treatment of infections caused by Aspergillus. In one embodiment, posaconazole can be adapted for the treatment of infections caused by zygomycetes. In some embodiments, posaconazole can be adapted to prevent infections in patients at high risk of developing invasive Aspergillus and Candida infections due to severe immunodeficiency, such as patients with graft-versus-host disease (GVHD) who have received hematopoietic stem cell transplantation (HSCT), and patients with hematological malignancies with long-term neutropenia due to chemotherapy. In one embodiment, posaconazole can be adapted for the treatment of zygomycosis. In one embodiment, posaconazole can be adapted for the treatment of allergic bronchopulmonary aspergillosis. In one embodiment, posaconazole can be adapted for the prevention and treatment of recurrent esophageal candidiasis following HIV infection. In one embodiment, posaconazole can be adapted for the treatment of Fusarium infections. In one embodiment, posaconazole can be adapted for the treatment of chronic or cavitary necrotizing pulmonary aspergillosis.

[0040]

[0049] As used herein, the term "CYP3A4 substrate drug" refers to a drug that is administered in a pharmaceutically acceptable dosage form (e.g., tablets, capsules, oral solutions, injections, infusions, sustained-release or extended-release formulations thereof) and is mainly metabolized by the CYP3A4 enzyme. 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, 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 lauroxil (Aristada). In some embodiments, the CYP3A4 substrate drug includes cariprazine hydrochloride (Vraylar). In some embodiments, the CYP3A4 substrate drug includessimeprevir sodium (Olysio). 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 some embodiments, the CYP3A4 substrate drug includes 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 includes tofacitinib citrate (Xeljanz). In some embodiments, the CYP3A4 substrate drug includes eletriptan hydrobromide (Relpax). In some embodiments, the CYP3A4 substrate drug includes nilotinib hydrochloride monohydrate (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 (Xarelto). 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 includes 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 (Emend). In some embodiments, the CYP3A4 substrate drug includes solifenacin succinate (VESIcare). In some embodiments, the CYP3A4 substrate drug includes erlotinib hydrochloride (Tarceva). In some embodiments, the CYP3A4 substrate drug includes ado-trastuzumab emtansine (Kadcycla). 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 includes cabozantinib S-malate S-malate (Cabometyx). In some embodiments, the CYP3A4 substrate drug includes 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 CYP3A4 substrate drug includes levomilnacipran hydrochloride (Fetzima). 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 ivacaftor / tezacaftor (Symdeko). In some embodiments, the CYP3A4 substrate drug includes regorafenib (Stivarga). In some embodiments, the CYP3A4 substrate drug includes daclatasvir (Daklinza). In some embodiments, the CYP3A4 substrate drug includes 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 grazoprevir (Zepatier). 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 includes 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 (Corlanor). In some embodiments, the CYP3A4 substrate drug includesivosidenib (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), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase, Forovase), tipranavir (Aptivus), etc.), benzodiazepines (alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), etc.), calcium antagonists (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), nifedipine (Procardia, Adalat), nilvadipine (Nivadil), nimodipine (Nimotop), soludipine (Baymycard, Sular, Syscor), nitrendipine (Cardif, Nitrepin, Baylotensin), pranidipine (Acalas), etc.), hydroxymethylglutaryl coenzyme A - reductase inhibitors (atorvastatin (Lipitor, Ator), lovastatin (Mevacor, Altocor, Altoprev), mevastatin (Compactin), simvastatin (Zocor, Lipex), etc.), anti - tumor drugs (sorafenib (Nexavar), sunitinib (Sutent), etc.), non - sedating anti - histamines (fexofenadine (Allegra), loratadine (Claritin), desloratadine (Clarinex), cetirizine (Zyrtec), levocetirizine (Xyza), etc.), immunosuppressants (cyclosporine, etc.), but are not limited to these.

[0041]

[0050] In some embodiments, the CYP3A4 substrate drug used in the methods disclosed herein is a drug metabolized by CYP3A4, particularly a drug metabolized by CYP3A4, and is prohibited from being used in combination with a potent CYP3A4 inhibitor, or a drug for which dosage adjustment is recommended for combined administration with a CYP3A4 inhibitor, regardless of the type. In some embodiments, the methods described herein are applied to treatment regimens used to treat patients in whom one or more of the CYP3A4 substrate drugs described herein have been pre-treated with posaconazole, for example, treatment regimens involving the treatment of patients who have combined a CYP3A4 substrate drug with other drugs.

[0042]

[0051] In some embodiments, the CYP3A4 substrate drug is used for the treatment of schizophrenia in adults and adolescents (13 - 17 years old), depressive episodes associated with type I bipolar disorder (bipolar depression) in adults and children (10 - 17 years old) (as monotherapy or as adjunctive therapy with lithium or valproic acid), 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 and older who are homozygous for the F508del mutation in the CFTR gene, chronic lymphocytic leukemia in patients with a deletion of the short arm of chromosome 17 who have received at least one prior treatment, unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a regimen containing anthracyclines previously, progressive or metastatic breast cancer in postmenopausal women with hormone receptor (HR) positivity, progressive or metastatic breast cancer negative for human epidermal growth factor receptor 2 (HER2), negative progressive or metastatic breast cancer (in combination with an aromatase inhibitor for postmenopausal women), Duchenne muscular dystrophy (DMD), secondary hyperparathyroidism (HPT) in dialysis patients with chronic kidney disease (CKD), hypercalcemia in patients with primary HPT or parathyroid cancer who are recommended parathyroidectomy based on serum calcium levels but are unable to undergo parathyroidectomy, hallucinations and delusions due to Parkinson's disease psychosis, schizophrenia, acute manic or mixed episodes associated with type I bipolar disorder, chronic hepatitis C (CHC) infection (as a component of a combination antiviral treatment regimen using peginterferon α and ribavirin for HCV genotype 1 - infected subjects with compensated liver disease), progressive hormone receptor - positive, HER2 - negative breast cancer (progressive HR+BC) in combination with exemestane after treatment failure with letrozole or anastrozole in postmenopausal women, progressive neuroendocrine tumors (PNET) of pancreatic origin, unresectable, locally progressive or metastatic well - differentiated non - functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, progressive renal cell carcinoma (RCC) (e.g., after treatment failure with sunitinib or sorafenib), renal angiomyolipoma and tuberous sclerosis complex (TSC) that do not require immediate surgery, TSC in patients with subependymal giant cell astrocytoma (SEGA) who require treatment intervention but are not candidates for surgical resection.Type 2 diabetes in adults (as an adjunct to diet and exercise therapy for improving blood glucose control), major depressive disorder (MDD), thrombotic cardiovascular events (such as 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 induce pulmonary embolism (PE) in patients who have undergone hip or knee replacement surgery, DVT, PE, recurrent DVT and PE associated with initial treatment, moderate to severe active rheumatoid arthritis in patients showing insufficient response or resistance to methotrexate, acute migraine with or without aura, chronic phase and accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in newly diagnosed patients or patients showing resistance or intolerance to pretreatment including imatinib, atrial fibrillation (AF) in patients with a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK) who are in sinus rhythm or have been defibrillated, asthma in patients 4 years of age and older, obstructive lung and exacerbation reduction in patients with chronic obstructive pulmonary disease, erectile dysfunction (ED), benign prostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHO group 1) (for the purpose of improving exercise capacity), gouty erythema, familial Mediterranean fever, antiretroviral therapy, anxiety disorder, panic disorder, seizures, insomnia, hypertension, cardiovascular disease, hyperlipidemia, primary renal cancer, progressive primary liver cancer, radioiodine-resistant progressive thyroid cancer, cancers such as renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor, mantle cell lymphoma in patients who have received at least one pretreatment, chronic lymphocytic leukemia / small lymphocytic lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma with deletion of the short arm of chromosome 17, Waldenström macroglobulinemia, marginal zone lymphoma in patients requiring systemic treatment and who have received at least one anti-CD20-based treatment, unresectable or metastatic melanoma with BRAF V600E or V600K mutation, allergy, transplantation, hormone-refractory metastatic prostate cancer treated with a treatment regimen previously containing docetaxel, a treatment regimen previously containing docetaxel, hormone-refractory metastatic prostate cancer treated for clinically significant polycythemia and normovolemic 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) containing high-dose 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 incontinence, urgency, and frequency, metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations detected by FDA-approved tests, and receiving first-line, maintenance, or second-line or greater treatment after progression, locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine, in patients who have previously received treatment for metastatic disease or have developed disease recurrence within 6 months of completion of adjuvant therapy, HER-2 positive metastatic breast cancer in patients who have previously received trastuzumab and taxanes separately or in combination, adult patients with chronic phase, accelerated phase, or acute phase Philadelphia chromosome-positive chronic myeloid leukemia (CML) with resistance or intolerance to previous treatment, 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-directed HIV-1 infection in patients 2 years of age and older weighing at least 10 kg in combination with other antiretroviral drugs, advanced renal cell carcinoma, advanced soft tissue sarcoma in patients who have previously received chemotherapy, manic and mixed episodes associated with type I bipolar disorder, major depressive disorder, hypersensitivity associated with autistic disorder, Tourette disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one previous systemic therapy, improving glycemic control in adults with type 2 diabetes mellitus (T2DM) with inadequate control by dapagliflozin or who are already being treated with dapagliflozin and saxagliptin, advanced metastatic medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC) in patients who have previously received anti-angiogenic therapy, chronic phase, accelerated phase, or acute phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in adults for whom other tyrosine kinase inhibitor (TKI) therapies are not indicated, adult patients with T315I-positive CML (chronic phase, accelerated phase, or acute phase) or T315I-positive Philadelphia chromosome,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 positive acute lymphoblastic leukemia (Ph+ALL), invasive aspergillosis, invasive mucormycosis, homozygous familial hypercholesterolemia (HoFH); adult schizophrenia; anastrozole as initial endocrine therapy in postmenopausal women, or fulvestrant in combination with endocrine therapy in women with disease progression after endocrine therapy, for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer; major depressive disorder (MDD); suppressing motor and vocal tics in patients with Tourette disorder who did not respond adequately to standard treatment; treating multiple myeloma in patients who have received at least two previous treatments including lenalidomide and a proteasome inhibitor and have shown disease progression within 60 days of completion of the last treatment; treating clinically significant polycythemia and euvolemic hyponatremia in patients with hormone-refractory metastatic prostate cancer, including those previously treated with a treatment regimen containing docetaxel, a treatment regimen containing docetaxel, heart failure, and syndrome of inappropriate antidiuretic hormone (SIADH); preventing acute and delayed nausea and vomiting associated with the initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) containing high-dose cisplatin; preventing delayed nausea and vomiting associated with the initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC); urge urinary incontinence, overactive bladder with symptoms of urgency and frequency; metastatic non-small cell lung cancer (NSCLC) with an exon 19 deletion or exon 21 (L858R) substitution mutation of the epidermal growth factor receptor (EGFR) detected by an FDA-approved test, for 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 in patients who have previously received trastuzumab and a taxane separately or in combination, during or within 6 months of completion of adjuvant therapy, in patients who have previously received treatment for metastatic disease or have developed disease recurrence; chronic phase, accelerated phase, with resistance or intolerance to previous treatment,Or adult patients with Ph+ chronic myeloid leukemia (CML) in the acute phase, gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC), patients with advanced well-differentiated pancreatic neuroendocrine tumor (pNET) with unresectable, locally advanced or metastatic disease, CCR5-directed HIV-1 infection in patients aged 2 years and older with a body weight of at least 10 kg in combination with other antiretroviral drugs, advanced renal cell carcinoma, advanced soft tissue sarcoma previously treated with chemotherapy, manic and mixed episodes associated with type I bipolar disorder, major depressive disorder, hypersensitivity associated with autistic disorder, Tourette disorder, agitation associated with schizophrenia or bipolar mania, advanced renal cell carcinoma after failure of one previous systemic therapy, improving glycemic control in adults with type 2 diabetes mellitus (T2DM) with inadequate control by dapagliflozin or already treated with dapagliflozin and saxagliptin, advanced metastatic medullary thyroid carcinoma (MTC), advanced renal cell carcinoma (RCC) previously treated with anti-angiogenic therapy, chronic phase, accelerated phase, or acute phase of chronic myeloid leukemia (CML) or Ph+ ALL in adults where other tyrosine kinase inhibitor (TKI) therapies are not applicable, adult T315I-positive CML (chronic phase, accelerated phase, or acute phase) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), invasive aspergillosis, invasive mucormycosis, 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 homozygous familial hypercholesterolemia (HoFH), adult schizophrenia, aromatase inhibitors as initial endocrine therapy in postmenopausal women, or fulvestrant in combination with endocrine therapy 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), suppressing motor and vocal tics in patients with Tourette disorder who did not respond adequately to standard treatment, treating multiple myeloma in patients who have received at least two previous treatments including lenalidomide and proteasome inhibitors and showed disease progression within 60 days after completion of the last treatment.Non-small cell lung cancer (NSCLC) in which the disease has not progressed after 4 cycles of platinum-based first-line chemotherapy, locally advanced or metastatic NSCLC after failure on at least 1 previous chemotherapy regimen, locally advanced, unresectable or metastatic pancreatic cancer, urge incontinence, overactive bladder with symptoms of urgency and frequency, progressive renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib, treatment intervention is required but therapeutic surgical resection, As a single-agent therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer associated with tuberous sclerosis (TS) not subject to resection, subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, tuberous sclerosis complex, endocrine therapy and disease progression after previous chemotherapy in the metastatic setting, in combination with fulvestrant for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy, cystic fibrosis (CF) in patients 2 years of age and older with one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene responsive to ivacaftor, based on clinical and / or in vitro assay data, germline BRCA-mutated advanced ovarian cancer in adult patients treated in three or more previous chemotherapy lines, primary myelofibrosis, post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis, intermediate- or high-risk myelofibrosis including, myelofibrosis in patients with polycythaemia vera showing an inadequate response to hydroxycarbamide or intolerance to hydroxycarbamide, as adjuvant therapy to antidepressants for the treatment of major depressive disorder (MDD), cystic fibrosis (CF) in patients 12 years of age and older who are homozygous for the F508del mutation or have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene responsive 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 anti-EGFR therapy in the case of RAS wild-type, locally advanced, unresectable or metastatic gastrointestinal stromal tumour (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 or without ribavirin, sofosbuvir, metastatic non-small cell lung cancer (NSCLC) patients with tumours detected by an FDA-approved test to be anaplastic lymphoma kinase (ALK) or ROS1 positive, patients with chronic pain related to a previous cancer or its treatment and not requiring frequent (e.g., weekly) opioid dose escalation, includingOpioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, unresectable or metastatic melanoma in patients with BRAF V600E mutation detected by an FDA-approved trial, unresectable or metastatic melanoma in patients with BRAF V600E or V600K mutation detected by an FDA-approved trial in combination with trametinib, BRAF V600E or V600K mutation detected by an FDA-approved trial, and adjuvant treatment for melanoma in patients with lymph node metastasis after complete resection, metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutation detected by an FDA-approved trial, locally advanced or metastatic anaplastic thyroid cancer (ATC) in patients with BRAF V600E mutation with 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, treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who are progressing on or 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 previous systemic therapies, treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two previous treatments, treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two previous systemic treatments, treatment in combination with binimetinib for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation detected by an FDA-approved trial, treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD) characterized by low sexual desire that is not due to coexisting medical or psychiatric conditions; relationship problems; or the effects of drugs or other pharmaceutical substances, sinus rhythm with a resting heart rate of 70 beats per minute or more, taking the maximum tolerated dose of a beta blocker or for whom the use of a beta blocker is contraindicatedReducing 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, treating adult patients with relapsed or refractory acute myeloid leukemia (AML) with a sensitive IDH1 mutation detected by an FDA-approved trial, treating patients with multiple myeloma who have received at least two previous regimens, including bortezomib and immunomodulatory agents, treating adult patients with locally advanced basal cell carcinoma (BCC) that has recurred after surgery or radiotherapy, or adult patients who are not candidates for surgery or radiotherapy, treating patients with unresectable or metastatic melanoma with a BRAF V600E mutation detected by an FDA-approved trial, and treating patients with Erdheim-Chester disease with a BRAF V600 mutation, and can be adapted for the treatment of diseases or conditions selected from the group consisting of.

[0043]

[0052] In some embodiments, the CYP3A4 substrate drug can be used as monotherapy or as adjuvant therapy with lithium or valproic acid for the treatment of schizophrenia in adults and adolescents (13 - 17 years old), and type I bipolar disorder (bipolar depression), moderate bipolar depression, severe bipolar depression, and depressive episodes associated with severe bipolar depression with acute suicidal ideation and behavior (ASIB) in adults and children (10 - 17 years old).

[0044]

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

[0045]

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

[0046]

[0055] In one embodiment, the CYP3A4 substrate drug can be adapted 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 pretreatment.

[0047]

[0056] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have previously received a regimen containing anthracycline, for example.

[0048]

[0057] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of progressive or metastatic breast cancer in postmenopausal women with hormone receptor (HR) positivity, or progressive or metastatic breast cancer negative for human epidermal growth factor receptor 2 (HER2). In a further embodiment, the CYP3A4 substrate drug can be adapted for the treatment of negative progressive 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 can be adapted for the treatment of Duchenne muscular dystrophy (DMD).

[0050]

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

[0051]

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

[0052]

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

[0053]

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

[0054]

[0063] In one embodiment, the CYP3A4 substrate drug can be adapted as a component of a combination antiviral treatment regimen using peginterferon alpha and ribavirin for the treatment of chronic hepatitis C (CHC) infection in HCV genotype 1-infected subjects with compensated liver disease.

[0055]

[0064] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of postmenopausal women with progressive hormone receptor-positive, HER2-negative breast cancer (progressive HR+BC), for example, in combination with exemestane after treatment failure with letrozole or anastrozole. In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with progressive pancreatic neuroendocrine tumors (PNETs). In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with unresectable, locally advanced or metastatic gastrointestinal (GI) or lung-derived progressive well-differentiated non-functional neuroendocrine tumors (NETs). In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with progressive renal cell carcinoma (RCC) after treatment failure with, for example, sunitinib or sorafenib. In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) who do not require immediate surgery. In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of TSC in patients with subependymal giant cell astrocytoma (SEGA) who require treatment intervention but are not candidates for surgical resection.

[0056]

[0065] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of adult type II diabetes, for example, as an adjunct to diet and exercise therapy for improving blood glucose control.

[0057]

[0066] In one embodiment, the CYP3A4 substrate drug can be adapted for reducing the incidence of thrombotic cardiovascular events (such as cardiovascular death, myocardial infarction, stroke) in patients with acute coronary syndrome (ACS).

[0058]

[0067] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of major depressive disorder (MDD).

[0059]

[0068] In one embodiment, the CYP3A4 substrate drug can be adapted for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In one embodiment, the CYP3A4 substrate drug can be adapted for the prevention of deep vein thrombosis (DVT) that may induce pulmonary embolism (PE) in patients who have undergone, for example, hip or knee joint replacement surgery. In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of DVT or PE. In one embodiment, the CYP3A4 substrate drug can be adapted for reducing the risk of recurrent DVT and PE associated with initial treatment.

[0060]

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

[0061]

[0070] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of acute migraine with or without aura.

[0062]

[0071] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML) in patients who are newly diagnosed or who have shown resistance or intolerance to pre-treatment including imatinib.

[0063]

[0072] In one embodiment, the CYP3A4 substrate drug can be adapted for reducing the risk of hospitalization due to atrial fibrillation (AF) in patients who have a history of paroxysmal or persistent atrial fibrillation or atrial flutter (AFK), are in a sinus rhythm state, or have been defibrillated.

[0064]

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

[0065]

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

[0066]

[0075] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of gouty erythema. In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of familial Mediterranean fever.

[0067]

[0076] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of mantle cell lymphoma in patients who have received at least one pretreatment. In one embodiment, the CYP3A4 substrate drug can be adapted for chronic lymphocytic leukemia / small lymphocytic lymphoma. In one embodiment, the CYP3A4 substrate drug can be adapted for chronic lymphocytic leukemia / small lymphocytic lymphoma with deletion of the short arm of chromosome 17.

[0068]

[0077] In one embodiment, the CYP3A4 substrate drug can be adapted for Waldenström macroglobulinemia.

[0069]

[0078] In one embodiment, the CYP3A4 substrate drug is suitable for marginal zone lymphoma in patients who require systemic treatment and have received at least one anti-CD20-based treatment.

[0070]

[0079] In one embodiment, the CYP3A4 substrate drug is suitable for chronic or metastatic melanoma with BRAF V600E or V600K mutations.

[0071]

[0080] In one embodiment, the CYP3A4 substrate drug is suitable for the treatment of hormone-refractory metastatic prostate cancer previously treated with a treatment regimen containing docetaxel.

[0072]

[0081] In one embodiment, the CYP3A4 substrate drug is suitable for the treatment of clinically significant polycythemia and euvolemic hyponatremia, including patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).

[0073]

[0082] In one embodiment, the CYP3A4 substrate drug is suitable for the prevention of acute and delayed nausea and vomiting associated with the initial and repeated courses of highly emetogenic cancer chemotherapy (HEC) containing high-dose cisplatin.

[0074]

[0083] In one embodiment, the CYP3A4 substrate drug is suitable for the prevention of delayed nausea and vomiting associated with the initial and repeated courses of moderately emetogenic cancer chemotherapy (MEC).

[0075]

[0084] In one embodiment, the CYP3A4 substrate drug is suitable for the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency.

[0076]

[0085] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that has an exon 19 deletion or exon 21 (L858R) substitution mutation of epidermal growth factor receptor (EGFR) detected by a test approved by the FDA and is receiving first-line treatment, maintenance treatment, or second-line or higher treatment after progression.

[0077]

[0086] In one embodiment, the CYP3A4 substrate drug can be applicable in combination with gemcitabine to the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

[0078]

[0087] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of patients with HER-2 positive metastatic breast cancer who have previously received trastuzumab and taxane separately or in combination and are in the period during or within 6 months after completion of adjuvant therapy and have previously received treatment for metastatic disease or have developed disease recurrence.

[0079]

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

[0080]

[0089] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate.

[0081]

[0090] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of progressive renal cell carcinoma (RCC) in patients with unresectable, locally advanced, or metastatic disease; progressive well-differentiated pancreatic neuroendocrine tumor (pNET).

[0082]

[0091] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of CCR5-directed HIV-1 infection only in patients 2 years of age or older weighing at least 10 kg, in combination with other antiretroviral drugs.

[0083]

[0092] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with progressive renal cell carcinoma.

[0084]

[0093] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with progressive soft tissue sarcoma who have previously received chemotherapy.

[0085]

[0094] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of acute manic and mixed episodes associated with type I bipolar disorder.

[0086]

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

[0087]

[0096] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of hypersensitivity associated with autistic disorder.

[0088]

[0097] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of Tourette's disorder.

[0089]

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

[0090]

[0099] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of progressive renal cell carcinoma after failure of one previous systemic therapy.

[0091]

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

[0092]

[0101] In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of patients with progressive metastatic medullary thyroid carcinoma (MTC).

[0093]

[0102] In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of patients with progressive renal cell carcinoma (RCC) who have previously received anti-angiogenic therapy.

[0094]

[0103] In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of adult patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in chronic, accelerated, or blast phase for whom other tyrosine kinase inhibitor (TKI) therapies are not indicated.

[0095]

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

[0096]

[0105] In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of invasive aspergillosis.

[0097]

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

[0098]

[0107] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of adult schizophrenia.

[0099]

[0108] In one embodiment, the CYP3A4 substrate drug can be adapted 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 initial endocrine therapy in postmenopausal women or fulvestrant in women with disease progression after endocrine therapy.

[0100]

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

[0101]

[0110] In one embodiment, the CYP3A4 substrate drug can be adapted for suppressing motor and vocal tics in patients with Tourette's disorder who have not responded adequately to standard treatment.

[0102]

[0111] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of multiple myeloma in patients who have received at least two previous treatments including lenalidomide and a proteasome inhibitor and have shown disease progression within 60 days of completion of the last treatment.

[0103]

[0112] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of non-small cell lung cancer (NSCLC) in which the disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.

[0104]

[0113] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of locally advanced or metastatic NSCLC after failure of at least one previous chemotherapy regimen.

[0105]

[0114] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of locally advanced, unresectable or metastatic pancreatic cancer.

[0106]

[0115] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency

[0107]

[0116] In one embodiment, the CYP3A4 substrate can be adapted for the treatment of advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib

[0108]

[0117] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) that requires treatment intervention but is not a candidate for therapeutic surgical resection

[0109]

[0118] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of renal angiomyolipoma and tuberous sclerosis

[0110]

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

[0111]

[0120] In one embodiment, the CYP3A4 substrate drug 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 following endocrine therapy and prior chemotherapy in the metastatic setting

[0112]

[0121] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of cystic fibrosis (CF) in patients 2 years of age and older who have one mutation in the CFTR gene that responds to ivacaftor, based on clinical and / or in vitro assay data

[0113]

[0122] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of adult patients with germline BRCA-mutated advanced ovarian cancer who have been treated with three or more previous lines of chemotherapy and who have harmful or suspected harmful conditions.

[0114]

[0123] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.

[0115]

[0124] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of patients with polycythemia vera who have shown an insufficient response to hydroxyurea or who are intolerant to hydroxyurea.

[0116]

[0125] In one embodiment, the CYP3A4 substrate drug can be adapted as adjuvant therapy to antidepressants for the treatment of major depressive disorder (MDD).

[0117]

[0126] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of schizophrenia.

[0118]

[0127] In one embodiment, the CYP3A4 substrate drug can be adapted for the treatment of cystic fibrosis (CF) patients 12 years of age 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.

[0119]

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

[0120]

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

[0121]

[0130] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.

[0122]

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

[0123]

[0132] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of 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.

[0124]

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

[0125]

[0134] In one embodiment, the CYP3A4 substrate drug can be applicable to the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation detected by an FDA-approved test.

[0126]

[0135] In one embodiment, the CYP3A4 substrate drug can be applicable in combination with trametinib to the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation detected by an FDA-approved test.

[0127]

[0136] In one embodiment, the CYP3A4 substrate drug can be adapted in combination with trametinib for the treatment of melanoma with BRAF V600E or V600K mutations detected by FDA-approved tests and patients with lymph node metastasis after complete resection.

[0128]

[0137] In one embodiment, the CYP3A4 substrate drug can be adapted in combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutations detected by FDA-approved tests.

[0129]

[0138] In one embodiment, the CYP3A4 substrate drug can be adapted in combination with trametinib for the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutations where there are no satisfactory local treatment options.

[0130]

[0139] In one embodiment, the CYP3A4 substrate drug can be adapted with or without ribavirin for the treatment of adult chronic HCV genotype 1 or 4 infections.

[0131]

[0140] Other examples of symptoms or diseases for which a CYP3A4 substrate drug may be prescribed include antiretroviral therapy, such as HIV / AIDS, anxiety disorders, panic disorders, seizures, insomnia, hypertension, cardiovascular diseases (e.g., myocardial infarction, stroke, and angina), hyperlipidemia, primary renal cancer, progressive primary liver cancer, radioiodine-resistant progressive thyroid cancer, cancers such as renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumors, allergies, transplantation, etc., but are not limited thereto.

[0132]

[0141] As described above, even after discontinuation of treatment with a potent CYP3A4 inhibitor (including, but not limited to, posaconazole), posaconazole accumulates in the patient's body and reduces or interferes with the metabolism of CYP3A4 substrate drugs. Thus, patients who have previously taken posaconazole and are subsequently treated with a CYP3A4 substrate drug are likely to have plasma levels of the CYP3A4 substrate drug that exceed those of patients who are not treated with posaconazole but have otherwise identical conditions. This specification describes, in various embodiments, treatment regimens for CYP3A4 substrate drugs that are applied for about 2 to 21 days after discontinuation of treatment with a potent CYP3A4 inhibitor (e.g., posaconazole) in patients who have received multiple doses of the potent CYP3A4 inhibitor. In some embodiments, the treatment regimen includes a treatment or prescription with a dose of 50% or less of the reference dose of the CYP3A4 substrate drug for about 2 to 21 days after discontinuation of posaconazole treatment. As used herein, a dose less than 50% of the reference dose of the CYP3A4 inhibitor can be any amount from 0% (i.e., no administration) to about 50% of the CYP3A4 inhibitor for 2 to 21 days. Thus, the treatment regimens disclosed herein include, in some embodiments, delaying the first administration of the CYP3A4 substrate drug for about 2 to 21 days after discontinuation of posaconazole treatment, or performing treatment with a reduced dose of the CYP3A4 substrate drug for about 2 to 21 days after discontinuation of posaconazole treatment. The methods described herein can be applied to patients who have taken posaconazole and have signs that can be improved with CYP3A4 substrate drug treatment, such as normal patients (normal metabolizers who are not obese), obese patients, poor metabolizers, intermediate metabolizers, or patients including combinations thereof.

[0133]

[0142] In some embodiments, from the discontinuation of posaconazole (i.e., the last dose in the posaconazole regimen) to the initiation of treatment with a CYP3A4 substrate drug (i.e., the first dose in a CYP3A4 regimen with any of the CYP3A4 substrate drugs described herein), from about 2 days to about 42 days must have elapsed, such as 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 sub-ranges thereof). In some embodiments, the patient is a "normal" patient (i.e., having "normal" CYP3A4 enzyme function (often referred to as a "normal metabolizer" in the art), a normal weight, e.g., a patient with a BMI in the range of 18.5 to 24.9). In other embodiments, the patient is a patient having one of the physiological characteristics described herein. For example, a patient considered obese and / or a patient in a state where the level of CYP3A4 enzyme activity is referred to as low activity or medium activity in the art.

[0134]

[0143] The "delay" or waiting period from the discontinuation or cessation of posaconazole treatment to the initiation of treatment with a CYP3A4 substrate drug can be considered the time elapsed from the discontinuation of posaconazole treatment to the first dose of treatment with a CYP3A4 substrate drug. One of ordinary skill in the art will generally understand that additional doses of the CYP3A4 substrate drug will then be administered or prescribed. However, the "delay" or "drug holiday" period described herein is strictly the time from the discontinuation of posaconazole treatment to the first dose of treatment with a CYP3A4 substrate drug.

[0135]

[0144] In an alternative embodiment, instead of delaying treatment with the CYP3A4 substrate drug, after discontinuation of posaconazole treatment, the CYP3A4 substrate drug is administered or prescribed at a dose of 50% or less of the reference dose (the amount described as the recommended dose for the patient in the FDA-approved label 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, 37% or less, 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 discontinuation of the posaconazole regimen.

[0136]

[0145] In a further alternative embodiment, depending on the CYP3A4 substrate drug, the patient may discontinue the posaconazole regimen at a dose less than 100% of the reference dose (the amount listed as the recommended dose for the patient on the label approved by the FDA for the CYP3A4 substrate drug), for example, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% (including all ranges and sub-ranges thereof) of the reference dose, and then be treated, or be prescribed, for at least about 2 to 42 days, for example, 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 sub-ranges thereof).

[0137]

[0146] In addition to methods of treating or prescribing treatment to a "normal" patient (e.g., a CYP3A4 normal metabolizer who is not obese), the present disclosure discloses a method of treating or prescribing treatment with a CYP3A4 substrate drug to a patient having at least one of the physiological characteristics described herein and who has received multiple doses of posaconazole. Treatment with the CYP3A4 substrate drug is initiated or prescribed to be initiated after the delay time described herein (or the first dose is initiated after stopping posaconazole treatment). Alternatively, as described herein, after stopping posaconazole treatment, it is carried out or prescribed to be carried out at a reduced dose (any amount less than 100% of the reference dose, including, for example, about 1 / 3, about 1 / 2, about 2 / 3 of the reference dose, but not limited thereto) for a certain period. The physiological characteristics of the patient include a decrease in liver enzyme function, particularly a decrease in CYP3A4 enzyme function (the patient is referred to as an intermediate metabolizer or a poor metabolizer of CYP3A4 in the art), and / or the body weight or body fat status described herein. In some embodiments, the patient may have characteristics of various body fat statuses. "Body fat status", "body fat characteristics", "obesity status", "obesity characteristics", and their derivatives and variations refer to at least seven characteristics (BMI, ideal body weight ratio, waist size, body fat percentage, android body fat percentage, gynoid body fat percentage, total body fat) as described herein. In some embodiments, the body fat status is referred to as obesity, and the patient is called obese or an obese patient.

[0138]

[0147] As described herein, the applicant of the present invention has found that a specific patient, that is, a patient having the specific physiological characteristics described herein, such as body fat status, body weight status, and / or liver metabolism enzyme status, after stopping posaconazole treatment, has a substantially high plasma level of posaconazole and / or, for example, the known or intended elimination half-life (t 1 / 2) Since it shows a longer half-life, after discontinuation of posaconazole treatment, place the deferral period described herein before treatment with a CYP3A4 substrate drug or before prescribing the first treatment with a CYP3A4 substrate drug, or as described herein, it has been found that it is necessary to adjust (reduce) the dose of the CYP3A4 substrate drug for a certain period after discontinuation of posaconazole treatment. In some embodiments, the deferral period or dose adjustment period, or the level of dose adjustment, is greater than the period / amount of deferral or dose reduction set for patients considered to be "normal" patients. When the plasma level of posaconazole is substantially high and / or, for example, shows a longer half-life compared to the expected elimination half-life (t 1 / 2 ) of posaconazole as described in the label of NOXAFIL, or patients who require a long deferral period, a long dose adjustment period, or a high level of dose adjustment include, for example, obese patients, such as those with a BMI of at least about 35, an ideal body weight ratio of at least about 150%, a waist size of more than about 42 inches, a body fat percentage of more than about 40%, an android body fat percentage of more than about 40%, a gynoid body fat percentage of more than about 40%, a total body fat of more than about 40 kg, having one or more of these characteristics, and in some cases, patients with liver dysfunction, such as those combined with active metabolism or low-active metabolism in CYP3A4. Alternatively, patients who are not obese (for example, various measured values of body fat status described herein are not considered to be in the range of obesity, that is, a BMI of less than about 35, an ideal body weight ratio of less than about 150%, a waist size of less than about 42 inches, a body fat percentage of less than about 40%, an android body fat percentage of less than about 40%, a gynoid body fat percentage of less than about 40%, a total body fat of less than about 40 kg), but have a disorder in liver metabolism function, such as patients considered to be active metabolizers or low-active metabolizers in CYP3A4, according to the applicant of the present invention, compared to what is expected for "normal" patients (that is, patients who do not show the specific physiological characteristics described herein) or compared to the recommended values in the label of NOXAFIL, the plasma level of posaconazole at steady state is high and / or the elimination half-life (t 1 / 2) is long, so after discontinuing posaconazole treatment and before starting treatment with a CYP3A4 substrate drug, it is necessary to set a longer washout period (as described herein). Alternatively, for the patient, after discontinuing posaconazole treatment and before starting treatment at a reduced dose (as described herein) compared to the reference dose of the CYP3A4 substrate drug, a longer period (in this technical field) should be set to minimize or avoid adverse effects such as QTc prolongation and other side effects of CYP3A4 substrate drugs well known in this technical field. Conventionally, in the case of patients with the above physiological characteristics, due to the effect of physiological characteristics on the steady-state plasma level of posaconazole and / or the elimination half-life, a longer "washout" period is required between the doses of posaconazole and the CYP3A4 substrate drug, or after discontinuing posaconazole administration, it is necessary to reduce the reference dose of the CYP3A4 substrate drug for a certain period to treat or prescribe treatment for the patient, which was not known at all.

[0139]

[0148] The activity level of the P450 isoenzyme that metabolizes drugs can vary from person to person. Classification criteria for metabolizers include, but are not limited to, allelic heterogeneity of the CYP540 isoenzyme gene. For example, the CYP3A4 gene has allelic heterogeneity, and using the expression of the CYP3A4*22 allele, a subject can be classified into a CYP3A4 low expressor (i.e., a person who has one copy of the CYP3A4*22 allele) and a CYP3A4 normal expressor (i.e., a person who does not have the CYP3A4*22 allele).

[0140]

[0149] In some embodiments, the patient treated by the method of the present disclosure has a body mass index (BMI, unit is kg / m unless otherwise defined) 2 ) of less than about 25, such as 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, less than about 19, or less than about 18.5 (including all ranges and subranges thereof).

[0141]

[0150] In some embodiments, a patient to be treated by the methods of the present disclosure has a body mass index (BMI, units are 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, at least 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 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 sub-ranges thereof). In one embodiment, the patient has a body mass index (BMI, units are kg / m unless otherwise defined) of at least about 35, 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 invention 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 (including all ranges and sub-ranges thereof) and is considered overweight or pre-obese. In some embodiments, the BMI of a patient is 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 (including all ranges and sub-ranges thereof) and is considered obese. In some embodiments, the BMI of a patient 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 sub-ranges thereof), and any of the BMIs described herein and 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 sub-ranges thereof).

[0143]

[0152] In some embodiments, a patient treated by the method of the present invention is a child or adolescent with a BMI of at least about the 85th percentile to at least about the 95th percentile, at least about the 86th percentile to at least about the 94th percentile, at least about the 87th percentile to at least about the 93rd percentile, at least about the 88th percentile to at least about the 92nd percentile, at least about the 89th percentile to at least about the 90th percentile (including all ranges and sub-ranges thereof), and any of the children or adolescents described herein, and is considered overweight or pre-obese. In some embodiments, the 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 sub-ranges thereof), and any of the BMI percentiles described herein, and is considered obese. In one embodiment, the patient is from about 5 years old to about 19 years old, or from about 7 years old to about 18 years old.

[0144]

[0153] In some embodiments, the patient treated by the methods of the present disclosure is a female patient in the first to third trimesters 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 (including all ranges and sub-ranges thereof), and is considered overweight or pre-obese. In some embodiments, the patient is a female patient in the first to third trimesters 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 (including all ranges and sub-ranges thereof), and is considered obese. In some embodiments, the patient treated by the methods of the present disclosure is a female patient in the first to third trimesters of pregnancy, with 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 sub-ranges thereof), and is considered severely obese.

[0145]

[0154] In some embodiments, methods for calculating BMI include, but are not limited to, weight (in kg) / (height in meters) 2 , weight (in pounds) / (height in inches) 2 × 703, etc.

[0146]

[0155] In some embodiments, the patient being treated by the methods of the present disclosure alternatively has 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 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 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 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 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 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 it can be described as having an ideal body weight ratio (%IBW) of at least about 280% (including all ranges and sub-ranges thereof) and any of the ideal body weight ratios (%IBW) described herein. In one embodiment, the patient has at least about 150% of the % ideal body weight (IBW). In one embodiment, the patient has at least about 250% of the % ideal body weight (IBW). In another embodiment, the patient has at least 150% of the %IBW and can be considered obese.,

[0147]

[0156] In some embodiments, a patient being treated according to the present disclosure can be described as having a waist size or torso circumference greater than 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 sub-ranges thereof), and any of the waist sizes or torso circumferences described herein. In one embodiment, a patient having a waist size or torso circumference of about 42 inches is considered obese. In other embodiments, the patient has a waist size or torso circumference greater than about 48 inches. In other embodiments, the patient's waist size or torso circumference is at least 42 inches.

[0148]

[0157] In some embodiments, a patient treated by the methods of the present disclosure can be described as having a body fat percentage greater than about 20%, 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% (including all ranges and sub-ranges thereof), and having any of the body fat percentages 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, patients with a body fat percentage greater than about 40% are considered obese. In some embodiments, the method of calculating body fat percentage includes, but is 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 has presented definitions of the "average" percentage of body fat as about 25-31% for women, about 18-24% for men, greater than or equal to about 32% for obese women, and greater than or equal to about 25% for obese men.

[0149]

[0158] In other embodiments, the patient may alternatively be described as having an android body fat percentage of 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%, greater than about 50%, greater than about 51%, greater than about 52%, greater than about 53%, greater than about 54%, greater than about 55%, greater than about 56%, greater than about 57%, greater than about 58%, greater than about 59%, greater than about 60%, greater than about 61%, greater than about 62%, 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 sub-ranges thereof), and having any of the android body fat percentages described herein. In one embodiment, a patient having an android body fat percentage of greater than about 40% can be considered obese. In one embodiment, a patient having an android body fat percentage of greater than about 50% can be considered obese.

[0150]

[0159] In other embodiments, the patient may alternatively be described as having an android body fat percentage of 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 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 sub-ranges thereof), and having any of the android body fat percentages described herein. In one embodiment, the patient has an android body fat percentage of at least about 50%.

[0151]

[0160] In other embodiments, the patient can alternatively be described as having a dinoid body fat percentage of 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%, greater than about 50%, greater than about 51%, greater than about 52%, greater than about 53%, greater than about 54%, greater than about 55%, greater than about 56%, greater than about 57%, greater than about 58%, greater than about 59%, greater than about 60%, greater than about 61%, greater than about 62%, 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 sub-ranges thereof), and having any of the dinoid body fat percentages described herein. In one embodiment, a patient having a dinoid body fat percentage of greater than about 40% can be considered obese. In one embodiment, a patient having a dinoid body fat percentage greater than about 50% can be considered obese.

[0152]

[0161] In other embodiments, the patient can alternatively be described as having a total body fat of more than about 30 kg, more than about 31 kg, more than about 32 kg, more than about 33 kg, more than about 34 kg, more than about 35 kg, more than about 36 kg, more than about 37 kg, more than about 38 kg, more than about 39 kg, more than about 40 kg, more than about 41 kg, more than about 42 kg, more than about 43 kg, more than about 44 kg, more than about 45 kg, more than about 46 kg, more than about 47 kg, more than about 48 kg, more than about 49 kg, more than about 50 kg, more than about 51 kg, more than about 52 kg, more than about 53 kg, more than about 54 kg, more than about 55 kg, more than about 56 kg, more than about 57 kg, more than about 58 kg, more than about 59 kg, more than about 60 kg, more than about 61 kg, more than about 62 kg, more than about 63 kg, more than about 64 kg, more than about 65 kg, more than about 66 kg, more than about 67 kg, more than about 68 kg, more than about 69 kg, more than about 70 kg, more than about 71 kg, more than about 72 kg, more than about 73 kg, more than about 74 kg, more than about 75 kg, more than about 76 kg, more than about 77 kg, more than about 78 kg, more than about 79 kg, more than about 80 kg, more than about 81 kg, more than about 82 kg, more than about 83 kg, more than about 84 kg, more than about 85 kg, more than about 86 kg, more than about 87 kg, more than about 88 kg, more than about 89 kg, more than about 90 kg, more than about 91 kg, more than about 92 kg, more than about 93 kg, more than about 94 kg, more than about 95 kg, more than about 96 kg, more than about 97 kg, more than about 98 kg, more than about 99 kg, more 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 sub-ranges thereof), and any total body fat described herein. In one embodiment, a patient having a total body fat of more than about 40 kg can be considered obese. In one embodiment, a patient having a total body fat of more than about 50 kg can be considered obese.

[0153]

[0162] In other embodiments, the obesity status of a patient treated by the methods of the present disclosure can be measured by waist-hip ratio. In other embodiments, the obesity status of a patient can be measured by skin thickness. In other embodiments, the obesity status of a patient can be measured by bioelectrical impedance. In other embodiments, the obesity status of a patient can be measured by underwater weighing or densitometry. In other embodiments, the obesity status of a patient can be measured by air displacement plethysmography. In other embodiments, the obesity status of a patient can be measured by dilution or specific gravity measurement. 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 published by the World Health Organization and the Centers for Disease Control (both of which are hereby incorporated by reference in their entirety for all purposes) can be employed to define obesity status, but are not limited thereto. For example, 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 normal as a BMI of 18.5 to less than 25, overweight as a BMI of 25.0 to less than 30, and obesity as a BMI of 30.0 or greater. The CDC further subdivides obesity into three classes, with a BMI of 30 to less than 35 being class 1, a BMI of 35 to less than 40 being class 2, and a BMI of 40 or greater being class 3. The CDC sometimes refers to class 3 obesity as "extreme" obesity, or "severe" obesity.

[0154]

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

[0155]

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

[0156]

[0165] In some embodiments, a patient may have four or more of the physiological indicators described herein. For example, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, and the body fat percentage is greater than about 40%. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, and the android body fat percentage is greater than about 40%. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, and the gynoid body fat percentage is greater than about 40%. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, and the total body fat is greater than about 43 kg. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the android body fat percentage is greater than about 40%. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the gynoid body fat percentage is greater than about 40%. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg. In some embodiments, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, the android body fat percentage is greater than about 40%, the gynoid body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg. In one embodiment, the patient's BMI is at least about 35, the ideal body weight ratio is at least 150%, the waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, the android body fat percentage is greater than about 40%, the gynoid body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg. In various other embodiments, the patient may have some or all of the specific physiological indicators described herein in combination.

[0157]

[0166] In some embodiments, the patient's waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the android body fat percentage is greater than about 40%. In some embodiments, the patient's waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the gynoid body fat percentage is greater than about 40%. In some embodiments, the patient's waist size is greater than about 42 inches, the body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg.

[0158]

[0167] In some embodiments, the patient's body fat percentage is greater than about 40%, the android body fat percentage is greater than about 40%, and the gynoid body fat percentage is greater than about 40%. In some embodiments, the patient's body fat percentage is greater than about 40%, the android body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg. In some embodiments, the patient's body fat percentage is greater than about 40%, the gynoid body fat percentage is greater than about 40%, and the total body fat is greater than about 40 kg. In some embodiments, the patient's android body fat percentage is greater than about 40%, the gynoid body fat percentage is greater than about 40%, and the total body fat is 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 patient having at least one of the obesity characteristics described herein is an intermediate metabolizer of CYP3A4. In some embodiments, a patient having at least one of the obesity characteristics described herein is a poor metabolizer of CYP3A4. In some embodiments, a patient having at least one of the obesity characteristics described herein is a normal metabolizer of CYP3A4. In other further embodiments, the patient is not obese, for example has a normal weight, but is an intermediate metabolizer or a poor metabolizer of CYP3A4.

[0160]

[0169] Alternatively, in some embodiments, the CYP3A4 genotype can be tested using targeted variant analysis. In some embodiments, the CYP3A4 genotype can be tested using sequence analysis of selected exons.

[0161]

[0170] In various embodiments, the present disclosure further discloses a method of treating a patient who has been pre-treated with posaconazole with a CYP3A4 substrate drug for which co-administration with a strong CYP3A4 inhibitor, such as posaconazole, is prohibited, wherein the CYP3A4 substrate drug has an AUC that is about 3000% or less of the normal baseline AUC of the CYP3A4 substrate drug (see the above definition), for example, 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 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, 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, about 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 335%, about 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, about 230% or less, about 225% or less, about 220% or lessMaintained at 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 sub-ranges). In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine maintains a level of about 150% or less of the normal baseline AUC of ranolazine. As used herein, the "normal baseline AUC of ranolazine" refers to the steady-state AUC measured for a specific dose of ranolazine in the absence of other drugs. 0-12 is shown. In some embodiments, the steady-state AUC 0-12 (%CV), when 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 (%CV), when measured after administration of 1000 mg of ranolazine, is 32,091 (42.2%) ng*h / mL. In other specific embodiments, the CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone maintains a level of about 216% or less of the normal baseline AUC of lurasidone. As used herein, the "normal baseline AUC of lurasidone" refers to the average AUC measured for a specific dose of lurasidone in the absence of other drugs 0-tau is shown. In some embodiments, the average AUC 0-tau , when measured after administration of 120 mg of lurasidone in a state of having a 350 kcal meal, is about 743 ng*h / mL. In other specific embodiments, the CYP3A4 drug is tadalafil, and the AUC of tadalafil maintains a level of about 410% or less of the normal baseline AUC of tadalafil. As used herein, the "normal baseline AUC of tadalafil" refers to the average AUC measured for a specific dose of tadalafil in the absence of other drugs 0-∞(%CV) is shown. In some embodiments, the mean AUC 0-∞ (%CV), when measured after administration of 10 mg of tadalafil, is about 3647 (34.0%) μg*h / L. In some embodiments, the mean AUC 0-∞ (%CV) is about 13,006 (43.9%) μg*h / L for 20 mg of tadalafil. In some embodiments, the mean AUC 0-∞ (%CV) is about 7,000 to about 13,000 (40.0%) μg*h / L for 20 mg of tadalafil. In other specific embodiments, the CYP3A4 substrate drug is erlotinib, and the AUC of erlotinib maintains a level of about 164% or less of the normal baseline AUC of erlotinib at 150 mg. As used herein, the "normal baseline AUC of erlotinib" refers to the mean AUC measured for a specific dose of erlotinib in the absence of other drugs 0-24 (%CV) is shown. In some embodiments, the mean AUC 0-24 (%CV), when measured after administration of 150 mg of erlotinib, is about 15.2 (400.0%) μg*h / mL. The AUC 0-24 (%CV) of erlotinib can vary widely and tends to increase in cancer patients compared to healthy volunteers. Thus, in some embodiments, the mean AUC 0-24(%CV) can be 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, about 35 μg*h / mL, about 36 μg*h / mL, about 37 μg*h / mL, about 38 μg*h / mL, about 39 μg*h / mL, about 40 μg*h / mL, about 41 μg*h / mL, about 42 μg*h / mL, about 43 μg*h / mL, about 44 μg*h / mL, about 45 μg*h / mL, about 46 μg*h / mL, about 47 μg*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 (including all ranges and sub-ranges thereof). In other specific embodiments, the CYP3A4 substrate drug is solifenacin succinate, and the AUC of solifenacin succinate maintains a level of about 270% or less of the normal baseline AUC of solifenacin succinate. As used herein, "the normal baseline AUC of solifenacin succinate" refers to the average AUC measured for a specific dose of solifenacin succinate in the absence of other drugs. 0-24 (%CV) is shown. In some embodiments, the average AUC at steady state 0-24(%CV) for 5 mg of solifenacin succinate is approximately 463 (37%) ng*h / mL. In some embodiments, the steady-state mean AUC 0-24 (%CV) for 10 mg of solifenacin succinate is approximately 749 (22%) ng*h / mL. In other specific embodiments, the CYP3A4 drug is everolimus, and the AUC of everolimus maintains a level of about 440% or less of the normal baseline AUC of everolimus. As used herein, the "normal baseline AUC of everolimus" is the mean AUC measured under steady-state conditions for a specific dose of everolimus in the absence of other drugs 0-24 ±SD is shown. In some embodiments, the mean AUC 0-24 ±SD, when measured after administration of 10 mg of everolimus, is approximately 536 ± 7.7 ng*h / L.

[0162]

[0171] In various other embodiments, the present disclosure is a method of treating a patient who has been pre-treated with posaconazole. As described herein, the method involves reducing (e.g., to about 10% - 90% of the reference dose) or prescribing a reduced dose of a CYP3A4 substrate drug whose co-administration with a strong CYP3A4 inhibitor is prohibited for about 2 to 42 days after discontinuing posaconazole treatment. The CYP3A4 substrate drug has an AUC that is about 3000% or less of the normal baseline AUC of the CYP3A4 substrate drug (see the above definition), e.g., 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 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, 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, 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 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% or less, about 275% or less,Maintained at 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, 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 sub-ranges). 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 of 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 of about 440% or less of the normal baseline AUC of everolimus.,

[0163]

[0172] In various embodiments, the present disclosure further discloses a method of treating a patient pre-treated with posaconazole with a CYP3A4 substrate drug that is prohibited from being used in combination with a potent CYP3A4 inhibitor, such as posaconazole, where the CYP3A4 substrate drug is C max to about 4000% or less of the normal baseline C of the CYP3A4 substrate drug, e.g., the normal baseline C of the CYP3A4 substrate drug max 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, 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 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, 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, 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 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% 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,Maintained at about 215% or less, about 210% or less, for example, 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 sub-ranges thereof). In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the C of ranolazine, max is maintained at a level of about 150% or less of the normal baseline C of ranolazine max . As used herein, "the normal baseline C of ranolazine max " refers to 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 (%CV) is 1081 (49.1%) ng / mL when measured after administration of 500 mg of ranolazine. In some embodiments, the steady-state C max (%CV) is 1955 (54.0%) ng / mL when measured after administration of 1000 mg of ranolazine. In other specific embodiments, the CYP3A4 substrate drug is lurasidone, and the C of lurasidone max is maintained at a level of about 210% or less of the normal baseline C of lurasidone max . As used herein, "the normal baseline C of lurasidone max " refers to the average C measured for a specific dose of lurasidone in the absence of other drugs max . In some embodiments, the average C max (%CV) is about 160 ng / mL when measured after administration of 120 mg of lurasidone in a state of having a 350 kcal meal. In other specific embodiments, the CYP3A4 substrate drug is tadalafil, and the C of tadalafil max is the normal baseline C of tadalafil maxMaintain a level of about 120% or less of max “the normal baseline C of tadalafil”. In this specification, “the normal baseline C max of tadalafil” refers to the average C max measured for a specific dose of tadalafil in the absence of other drugs. In some embodiments, the average C max (%CV) is about 190 (21.7%) μg / L when measured after administration of 10 mg of tadalafil. In some embodiments, the average C max (%CV) is about 548 (24.0%) μg / L when measured after administration of 20 mg of tadalafil. In other specific embodiments, the CYP3A4 substrate drug is erlotinib, and the C max of erlotinib maintains a level of about 167% or less of the normal baseline C max of 150 mg of erlotinib. In this specification, “the normal baseline C max of erlotinib” refers to the average C max measured for a specific dose of erlotinib in the absence of other drugs. In some embodiments, the average C max (%CV) at steady state is 1.7 (90%) μg / mL when measured after administration of 150 mg of erlotinib. The C 0-24 of erlotinib can vary widely and tends to increase in cancer patients compared to healthy volunteers. Thus, in some embodiments, the average AUC 0-24(%CV) can be 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 sub-ranges thereof). In other specific embodiments, the CYP3A4 substrate drug is solifenacin succinate, and C max of solifenacin succinate maintains a level of about 150% or less of the normal baseline C max of solifenacin succinate. As used herein, "the normal baseline C max of solifenacin succinate" refers to the average C max measured for a specific dose of solifenacin succinate in the absence of other drugs. In some embodiments, the average C max (%CV) measured after administration of 5 mg of solifenacin succinate is 24.01 (30%) ng / mL. In some embodiments, the average C max (%CV) measured after administration of 10 mg of solifenacin succinate is 40.61 (21%) ng / mL. In other specific embodiments, the CYP3A4 drug is everolimus, and C max of everolimus maintains a level of about 200% or less of the normal baseline C max of everolimus. As used herein, "the normal baseline C max of everolimus" refers to the average C maxis shown. In some embodiments, the average C max (%CV), when measured after administration of 10 mg of everolimus, is 59.7 ± 16.9 (21.7%).

[0164]

[0173] In various other embodiments, the present disclosure reduces the dose of a CYP3A4 substrate drug, the co-administration of which with a potent CYP3A4 inhibitor is prohibited, for at least about 2 days to at least about 42 days after discontinuation of posaconazole treatment (e.g., about 10% - 50% of the reference dose), and discloses a method of treating a patient who has previously taken posaconazole, and the CYP3A4 substrate drug is C max to the normal baseline C of the CYP3A4 substrate drug max of about 4000% or less, e.g., the normal baseline C of the CYP3A4 substrate drug 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, 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 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, 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, 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 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% 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 215% or lessMaintained at 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 sub - ranges). In a specific embodiment, the CYP3A4 substrate drug is ranolazine, and the C of ranolazine, max maintains a level of about 150% or less of the normal baseline C of ranolazine. In other specific embodiments, when the CYP3A4 substrate drug is lurasidone, the C of lurasidone max maintains a level of about 210% or less of the normal baseline C of lurasidone. In other specific embodiments, when the CYP3A4 substrate drug is tadalafil, the C of tadalafil max maintains a level of about 120% or less of the normal baseline C of tadalafil. In other specific embodiments, when the CYP3A4 substrate drug is erlotinib, the C of erlotinib max maintains a level of about 167% or less of the normal baseline C of erlotinib. In other specific embodiments, when the CYP3A4 substrate drug is solifenacin succinate, the C of solifenacin succinate max maintains a level of about 150% or less of the normal baseline C of solifenacin succinate. In other specific embodiments, when the CYP3A4 substrate drug is everolimus, the C of everolimus max maintains a level of about 200% or less of the normal baseline C of everolimus. max maintains a level of about 167% or less of the normal baseline C of erlotinib. In other specific embodiments, when the CYP3A4 substrate drug is solifenacin succinate, the C of solifenacin succinate max maintains a level of about 150% or less of the normal baseline C of solifenacin succinate. In other specific embodiments, when the CYP3A4 substrate drug is everolimus, the C of everolimus max maintains a level of about 150% or less of the normal baseline C of solifenacin succinate. In other specific embodiments, when the CYP3A4 substrate drug is everolimus, the C of everolimus max maintains a level of about 150% or less of the normal baseline C of solifenacin succinate. In other specific embodiments, when the CYP3A4 substrate drug is everolimus, the C of everolimus max maintains a level of about 200% or less of the normal baseline C of everolimus. max maintains a level of about 200% or less of the normal baseline C of everolimus.

[0165]

[0174] CYP3A4 substrate drugs (such as lurasidone and ranolazine) have labels that prohibit co-administration with potent CYP3A4 inhibitors such as posaconazole. Thus, conventionally, it would be considered safe to administer a CYP3A4 substrate drug one day after the last dose of posaconazole (i.e., one day after discontinuing or "stopping" posaconazole). However, the interaction between posaconazole and many CYP3A4 substrate drugs has not been investigated in the past. The applicant's clinical study is the first study to observe the levels of specific CYP3A4 substrate drugs during co-administration of posaconazole and over a long period after posaconazole administration has been discontinued. The applicant has found that the inhibitory effect of posaconazole on CYP3A4 persists substantially longer than predicted from its half-life, and thus posaconazole inhibits the metabolism of CYP3A4 substrate drugs for a substantially longer period than predicted from the prior art. Thus, the actual plasma concentration of the CYP3A4 substrate drug is in fact significantly higher after discontinuing posaconazole than was predicted from the prior art. Thus, to achieve a "safe" plasma concentration profile of the CYP3A4 substrate drug (e.g., when the benefit of treating a patient for a condition or disease to which the CYP3A4 substrate drug is indicated outweighs the risk associated with the effects of drug-drug interactions as described herein), the applicant has found that the patient must wait longer (e.g., longer than the one-day contraindication period provided in the label) and / or administer a reduced dose of the CYP3A4 substrate drug than was previously considered.

[0166]

[0175] For the purposes of the present method, the predicted plasma levels of a CYP3A4 substrate drug after discontinuation of co - administration with a potent CYP3A4 inhibitor such as posaconazole or ketoconazole can be calculated from the plasma levels of the CYP3A4 substrate drug during co - administration with the potent CYP3A4 inhibitor using conventional pharmacological methods as follows. Plasma levels can be described in various ways, such as the area under the plasma concentration curve (AUC) and the peak plasma concentration (Cmax). The baseline level and the posaconazole interaction level of a CYP3A4 substrate drug 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 a patient population that is otherwise identical at other points where no CYP3A4 inhibitor is being administered. GMR is a standard industry and regulatory method for evaluating the ratio of the change in a pharmacokinetic variable (such as AUC) to its own baseline value (e.g., in patients not treated with posaconazole). If the level (AUC or Cmax) of the substrate drug during co - administration of posaconazole and the CYP3A4 substrate drug is known, 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 discontinuation of posaconazole administration. Such a function can be used to provide a plot of the decay GMR of the AUC (or Cmax) of the CYP3A4 substrate drug over time due to interaction with posaconazole, based on the stated half - life of posaconazole. As the GMR curve approaches the time at which essentially all of the posaconazole is predicted to be eliminated by its known half - life, the GMR approaches a value of 1.

[0167]

[0176] One of ordinary skill in the art will understand that the predicted 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): (x)th day AUC GMR = 1 + [(AUC during co - administration) - 1]*e^(-K el *x) (Equation 1) Wherein, K el = ln(2) / (31 hours / 24 hours) or approximately 0.5366, based on the 31 - hour half - life of posaconazole tablets (Noxafil® label updated in September 2016), and Wherein, x is the number of days after discontinuation of posaconazole.

[0168]

[0177] The predicted DDI decay curve can also be calculated for Cmax GMR by replacing the AUC during co - administration in Equation 1 with the Cmax at co - administration. As used herein, terms such as "predicted level" and "forecast level" refer to the AUC or Cmax GMR values calculated using Equation 1.

[0169]

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

[0170]

[0179] The Applicant surprisingly and unexpectedly found that the plasma levels of CYP3A4 substrate drugs administered after posaconazole was discontinued were significantly increased compared to the predicted levels of such drugs calculated using Formula 1. Thus, the Applicant found that the inhibitory effect of posaconazole on CYP3A4 substrate drugs persists much longer than previously known, and that after posaconazole is discontinued, when a full standard dose of a CYP3A4 substrate drug is administered (e.g., as taught in the label of the CYP3A4 substrate drug described herein), plasma levels of the CYP3A4 substrate drug that are actually achieved are higher than the predicted levels (see Figures 8 and 9; dashed lines), for example, calculated using Formula 1. To address the clinical implications of this unexpected increase in plasma levels, the Applicant found that (i) the full standard dose of the CYP3A4 substrate drug should be administered more than 2 days after posaconazole is discontinued (e.g., as described herein) to achieve a safe plasma level that is higher than predicted, or (ii) the dose of the CYP3A4 substrate drug should be reduced to administer a drug at a safe plasma level that is approximately equivalent (e.g., about 80 - 125%) to the level predicted from the full standard dose of the CYP3A4 substrate drug based on the above equation. The reduced dose of the CYP3A4 substrate drug can be administered with posaconazole the day after posaconazole is discontinued, or more than 2 days after posaconazole is discontinued (e.g., as described herein).

[0171]

[0180] In some embodiments (e.g., when a full dose is administered more than 2 days after posaconazole is discontinued, or when a reduced dose as described herein is administered), the plasma levels of the CYP3A4 substrate drug are therapeutic and below the target levels considered safe (i.e., here, inhibition of CYP3A4 by posaconazole will not pose an unacceptable risk of serious side effects to the patient). In FIG. 10, a line indicating the target AUC GMR level of encorafenib considered safe according to some embodiments is overlaid on this figure. The present disclosure provides a method of administering encorafenib to achieve plasma levels that are higher than the predicted levels but do not exceed the target safety levels. Thus, in various embodiments, the method comprises (i) after discontinuing posaconazole, administering a reference dose of a CYP3A4 substrate drug (such as encorafenib) for 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, or 42 days) to achieve plasma levels that are above the levels predicted from the 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) but do not exceed the target safety level, or (ii) administering a reduced dose to achieve plasma levels that are above the levels calculated for the full reference dose but do not exceed the target safety level.

[0172]

[0181] For lurasidone, ranolazine, and encorafenib, the predicted DDI decay curves of the plasma levels of other CYP3A4 substrate drugs can be calculated, for example, using Equation 1, from the plasma levels of the CYP3A4 substrate drugs obtained during co - administration with posaconazole and the conventionally understood half - life of posaconazole. Table A below contains: (a) the co - administration levels of CYP3A4 substrate drugs in the columns titled "AUC co - administration level" and "Cmax co - administration level"; (b) "AUC target safety level" and "Cmax target safety level" (levels at which, according to some embodiments, the benefit outweighs the risk); and (c) the "baseline AUC" and "baseline Cmax" levels of CYP3A4 substrate drugs measured in patients not previously treated with a potent CYP3A4 inhibitor (e.g., posaconazole). The column titled "co - administration level" provides the fold change or percentage of the baseline increase observed when the substrate drug was co - administered with a potent CYP3A4 inhibitor (e.g., ketoconazole). Since co - administering many of these CYP3A4 substrate drugs with a potent CYP3A4 inhibitor is contraindicated, the co - administration levels represent Cmax and AUC levels that are not safe. In various embodiments, the "target safety level" is, in some embodiments, an upper limit of fold change or a non - limiting example of a percentage of the baseline when the benefit of treating a patient for a condition or disease to which the CYP3A4 substrate drug is applied outweighs the risk associated with the impact of the drug - drug interaction. Table A provides an example of the target safety 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" indicates the plasma concentration of the CYP3A4 substrate drug in the same patient except that no potent CYP3A4 inhibitory drug has been administered. The co - administration levels reported in Table A were measured with either posaconazole, itraconazole, ritonavir, or ketoconazole. For the purposes of this method, the plasma levels measured during co - administration of a CYP3A4 substrate drug with ketoconazole can be used, for example, using Equation 1, to estimate the posaconazole DDI decay curve.In some embodiments, the present disclosure provides a method of administering a CYP3A4 substrate drug to achieve plasma levels that are below the target safety AUC and Cmax shown in Table A. To be able to calculate an appropriate delay period and / or a reduced dosing period, the plasma levels of the CYP3A4 substrate drug can be measured using conventional methods known in the art to determine when the plasma levels are within safe and effective levels (e.g., obtaining a blood sample from a patient and measuring the plasma concentration of the CYP3A4 substrate drug using mass spectrometry). In the following sections, applicant's surprising and unexpected information regarding CYP3A4 inhibition by posaconazole collected from applicant's clinical studies will be considered with respect to how to report 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 values. In some embodiments, the percent-based baselines of the AUC and Cmax target safety levels 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 achieved AUC or Cmax level can be 155% or 105%. Similarly, in some embodiments, the GMR of AUC or Cmax can vary by about +25%.

[0181]

[0183] The potentially harmful consequences of leaving a patient untreated with a CYP3A4 substrate drug must be balanced against the potential risks associated with the effects of DDI between the CYP3A4 substrate drug and posaconazole (e.g., increased plasma levels and increased exposure to the CYP3A4 substrate drug), such that a person of ordinary skill in the art (e.g., a physician) will administer the dose of the CYP3A4 substrate drug as soon as administration is safe. For example, a physician will administer the CYP3A4 substrate drug as soon as a clinically significant increase in plasma levels, or exposure to the CYP3A4 drug beyond a target level considered safe, ceases to occur. Even though lower plasma levels of posaconazole reduce the potential adverse effects of DDI, such a physician will not wait a longer period because the patient does not receive the benefits of treatment with the CYP3A4 substrate drug (or remains at risk associated with remaining untreated). For certain CYP3A4 substrate drugs, the CYP3A4 substrate drug is contraindicated for co-administration with posaconazole. Accordingly, a person of ordinary skill in the art will interpret such a contraindication to mean that co-administration of the CYP3A4 substrate drug with a CYP3A4 inhibitor (e.g., posaconazole) is only unsafe, but it is safe to administer 100% of the reference dose (as defined herein) of the CYP3A4 substrate drug immediately on the day following the last dose of posaconazole (i.e., the day following the "cessation" of posaconazole).

[0182]

[0184] However, Applicants have found that the inhibitory effect of posaconazole on CYP3A4 persists substantially longer than predicted from its half-life. Applicants have also found that the levels of posaconazole remain higher than expected over a long period of time for the obese patients defined herein. See Figure 8, which shows that the actual lurasidone AUC levels (dashed line) measured in patients after discontinuation of posaconazole are unexpectedly higher than the levels predicted by the prior art from the posaconazole half-life (solid line) after discontinuation of posaconazole. Also see 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 results in an increased risk of causing serious side effects in subsequent administrations of CYP3A4 substrate drugs, which has not been previously recognized. To reduce this risk, in some embodiments, the administration of CYP3A4 substrate drugs is contraindicated not only for co-administration with posaconazole, but also for administration for a certain period (e.g., 2 days or more) after discontinuation of posaconazole beyond the 1-day delay indicated on the label (i.e., contraindication for co-administration of CYP3A4 substrate drugs and posaconazole). In some embodiments, the method provides for administering a CYP3A4 substrate drug as soon as administration is safe, e.g., for a period exceeding about 1 day, as described herein. Administering a CYP3A4 substrate drug "as soon as it is safe" does not mean waiting until all or almost all of the posaconazole has been eliminated from the patient to minimize DDI. Rather, administering a CYP3A4 substrate drug "as soon as it is safe" generally means administering the CYP3A4 substrate drug even when the plasma levels of posaconazole are at levels where an apparent DDI effect still exists. The CYP3A4 substrate drug is administered as soon as the effect of the DDI is low enough so that the plasma levels of the CYP3A4 substrate drug do not exceed the target safety level. This explains the need to treat patients with CYP3A4 substrate drugs without unnecessary delay (after discontinuation of posaconazole) to minimize the risk of leaving such patients untreated.

[0183]

[0185] As used herein, "safe", as used when a CYP3A4 substrate drug is administered "as soon as it is safe" and at "safe levels", means that inhibition of CYP3A4 by posaconazole ceases to pose an unacceptable risk of serious side effects to the patient (e.g., due to the plasma level of the CYP3A4 substrate drug). An "unacceptable risk of serious side effects" occurs, for example, when the risk associated with increased exposure to the CYP3A4 substrate drug is, overall, higher than the risk of not treating the patient with the CYP3A4 substrate drug. In some embodiments, as unexpectedly discovered by the applicant, administering the CYP3A4 substrate drug "as soon as it is safe" requires waiting longer than predicted by the prior art (i.e., waiting more than 1 day after discontinuing posaconazole, based on the labeling contraindication of co - administration of the CYP3A4 substrate drug and posaconazole). Implicitly, "not safe" as used herein means that the risk associated with treating the patient (e.g., high exposure to the CYP3A4 substrate drug) is greater than the risk of not treating the patient. Thus, the method accounts for the previously unknown magnitude and unknown duration of the inhibitory effect of posaconazole on CYP3A4, as well as the need to treat the patient with the CYP3A4 substrate drug.

[0184]

[0186] In some embodiments, the CYP3A4 substrate drug is administered as soon as a treatment provides a favorable risk / benefit profile. The risk / benefit profile weights the patient's risk of potential adverse events upon treatment relative to the benefits of the 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 probability that the patient will experience one or more benefits; (iv) the duration of the effect and whether the duration is beneficial; (v) the severity, type, number, and rate of adverse events (e.g., severe adverse events vs. non-severe adverse events); (vi) the probability of adverse events (e.g., the percentage of the patient population expected to experience an adverse event; the incidence rate of each adverse event in the study population; the degree of uncertainty in the determination probability; the patient's willingness to accept the assumed risk of adverse events considering the assumed benefit); (vii) the duration of the adverse event (e.g., how long the adverse event will last and whether it is reversible; the type of intervention required to address the adverse event); (viii) medical necessity (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 dosing of the CYP3A4 substrate drug in the presence of a CYP3A4 inhibitor requires balancing various risk and benefit factors (e.g., as described above). The appropriate dosage of the CYP3A4 substrate drug resulting from the evaluation of the risk / benefit profile is customarily incorporated into the FDA-approved drug label. For the sake of clarity, an increase in PK (e.g., Cmax, AUC, or the GMR of AUC or Cmax) is not considered the only factor relevant when a person of ordinary skill in the art (e.g., a physician) decides whether to administer a CYP3A4 substrate drug. In some embodiments, as soon as the benefit outweighs the risk, the patient is administered the CYP3A4 substrate drug. In some embodiments, as soon as the benefit outweighs the risk, the patient is administered the full reference dose. In some embodiments, as soon as the benefit outweighs the risk, the patient is administered a reduced dose.

[0185]

[0187] In some embodiments, the CYP3A4 substrate drug is administered as soon as at least one of the Cmax, AUC, and GMR of AUC or Cmax of the CYP3A4 substrate drug reaches 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, for example, 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%, or about 95% lower than the co-administration level. In some embodiments, the CYP3A4 substrate drug is administered as soon as at least one of the Cmax, AUC, mean AUC, and GMR of AUC or Cmax of the CYP3A4 substrate drug increases to a level that was not predicted (e.g., higher than the predicted level) (based on an understanding of the impact of a conventional CYP3A4 inhibitor (e.g., posaconazole) on such levels of the CYP3A4 substrate drug, a level that was actually thought likely to occur).In some embodiments, the CYP3A4 substrate drug can be safely administered as soon as the Cmax or AUC of the CYP3A4 substrate drug reaches 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 1100%, about 1000%, about 990%, about 980%, about 970%, about 960%, about 950%, about 940%, about 930%, about 920%, about 910%, about 900%, about 590%, about 580%, about 570%, about 560%, about 550%, about 540%, about 530%, about 520%, about 510%, about 500%, about 490%, about 480%, about 470%, about 460%, about 450%, about 440%, about 430%, about 420%, about 410%, about 400%, about 390%, about 380%, about 370%, about 360%, about 350%, about 340%, about 330%, about 320%, about 310%, about 300%, about 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% (including all ranges and sub-ranges thereof) of the respective normal baseline values (Table A) of such parameters after the discontinuation of posaconazole. 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 the discontinuation of posaconazole.In some embodiments, immediately when the GMR of the AUC or Cmax of the CYP3A4 substrate drug becomes 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 9.8-fold, about 9.7-fold, about 9.6-fold, about 9.5-fold, about 9.4-fold, about 9.3-fold, about 9.2-fold, about 9.1-fold, about 9-fold, about 8.9-fold, about 8.8-fold, about 8.7-fold, about 8.6-fold, about 8.5-fold, about 8.4-fold, about 8.3-fold, about 8.2-fold, about 8.1-fold, about 8.0-fold, about 7.9-fold, about 7.8-fold, about 7.7-fold, about 7.6-fold, about 7.5-fold, about 7.4-fold, about 7.3-fold, about 7.2-fold, about 7.1-fold, about 7.0-fold, about 6.9-fold, about 6.8-fold, about 6.7-fold, about 6.6-fold, about 6.5-fold, about 6.4-fold, about 6.3-fold, about 6.2-fold, about 6.1-fold, about 6.0-fold, about 5.9-fold, about 5.8-fold, about 5.7-fold, about 5.6-fold, about 5.5-fold, about 5.4-fold, about 5.3-fold, about 5.2-fold, about 5.1-fold, about 5.0-fold, about 4.9-fold, about 4.8-fold, about 4.7-fold, about 4.6-fold, about 4.5-fold, about 4.4-fold, about 4.3-fold, about 4.2-fold, about 4.1-fold, about 4.0-fold, about 3.9-fold, about 3.8-fold, about 3.7-fold, about 3.6-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), the CYP3A4 substrate drug can be safely administered. In some embodiments, the CYP3A4 substrate drug can be safely administered immediately when it 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, 41, or 42 days (including all values and ranges therebetween) after the discontinuation of posaconazole.In some embodiments, the patient is administered the full standard dose of the CYP3A4 substrate drug to achieve either the Cmax or AUC value, or either the multiple change in GMR of the Cmax or AUC. In some embodiments, after discontinuation of posaconazole, the patient is administered a reduced dose of the CYP3A4 substrate drug to achieve either the Cmax or AUC value, or either the multiple change in GMR of the Cmax or AUC.

[0186]

[0188] In one embodiment, the methods disclosed herein are based on the conventionally understood half-lives of posaconazole of 27 hours (patients with normal liver function), 39 hours (patients with mild liver impairment), 27 hours (patients with moderate liver impairment), and 43 hours (patients with severe liver impairment), about 24 hours after administration by posaconazole injection, about 31 hours after administration of posaconazole delayed-release tablets, and about 31 - 37 hours after administration of posaconazole oral suspension, and provide 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. Noxafil® label, revised September 2016. Figure 8 shows the actual lurasidone AUC levels resulting from administration of 100% of the reference dose in normal weight and obese patients at various time points after posaconazole discontinuation, compared to the predicted lurasidone levels ( "predicted levels; practice") from the half-life of posaconazole described in the Noxafil® label using Equation 1 and a 31-hour posaconazole half-life (multiples of baseline AUC; dashed line). The solid line indicates that the predicted lurasidone AUC levels (reported as GMR) are approximately 400% (or about 4-fold) greater than baseline 1 day after posaconazole discontinuation, approximately 300% (or about 3-fold) greater than baseline 2 days after posaconazole discontinuation, approximately 200% (or about 2-fold) greater than baseline 3 days after posaconazole discontinuation, and then taper down to reach baseline by approximately day 9 after posaconazole discontinuation. In contrast, the applicant's data show that the actual lurasidone AUC levels are significantly higher than the predicted levels for at least 14 days after posaconazole discontinuation, e.g., approximately 2-fold greater than expected 2 days after posaconazole discontinuation, approximately 2 - 3-fold greater than expected 3 days after posaconazole discontinuation, approximately 2.5 - 3.5-fold greater than expected 4 days after posaconazole discontinuation, and maintain at approximately 2 - 3-fold the predicted level for at least about 14 days. The same study was conducted with ranolazine.Similar to FIG. 8, FIG. 9 shows the actual ranolazine AUC levels (as a multiple of the baseline AUC; dashed line) in normal weight and obese patients due to administration of 100% of the reference dose at various time points after posaconazole discontinuation, compared to the ranolazine levels predicted from the 31-hour half-life of posaconazole described in the Noxafil® label (“predicted levels”; practice). The applicant's data shows that the actual ranolazine AUC levels are significantly above the predicted levels for at least 14 days after posaconazole discontinuation. For example, two days after posaconazole discontinuation, it is approximately 0.5 to 1.5 times greater than expected, three days after posaconazole discontinuation, it is approximately 1.5 times greater than expected, four days after posaconazole discontinuation, it is approximately 1.5 times greater than expected, and it maintains at about 0.5 to 1.5 times the predicted level for at least about 14 days. In some embodiments, the method administers 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 predicted levels measured for the reference dose.

[0187]

[0189] In some embodiments, the method provides for administering lurasidone on a particular day after posaconazole has been discontinued, such that at least one of the AUC, Cmax, and / or GMR of AUC or Cmax of lurasidone exceeds a predicted level (e.g., a DDI decay curve calculated using Equation 1 and the recognized half-life of posaconazole) as shown in FIG. 8. In some embodiments, lurasidone is administered when at least one of the AUC or Cmax of lurasidone 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%, 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) of the baseline level.In some embodiments, lurasidone is administered when at least one of the GMR of the AUC or Cmax of lurasidone increases 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, 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 2.65-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 reference dose or a reduced dose) is initiated immediately after discontinuation of posaconazole, 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, or 42 days (including all values and sub-ranges therebetween).

[0188]

[0190] In some embodiments, the method provides for administering ranolazine on a particular day after posaconazole has been discontinued, such that at least one of the AUC, Cmax, and / or GMR of AUC or Cmax of ranolazine, as shown in FIG. 9, exceeds a predicted level (e.g., a DDI decay curve calculated using Equation 1 and the recognized 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% (including all values and ranges therebetween) of the baseline level. In some embodiments, ranolazine is administered when at least one of the GMR of AUC or Cmax of ranolazine increases 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 reference dose or a reduced dose) is initiated immediately after discontinuation of posaconazole, for 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).

[0189]

[0191] Observations of the applicant's clinical studies of lurasidone and ranolazine indicate that the administration of other CYP3A4 substrate drugs should not be made until at least 2 days after the discontinuation of posaconazole (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 later). In some embodiments, the applicant has found that after the levels of one or more of Cmax, AUC, and / or the GMR of AUC or Cmax of the CYP3A4 substrate drug have risen to levels that could not be predicted (e.g., the DDI decay curve calculated using Equation 1 and the observed half-life of posaconazole) after the discontinuation of posaconazole, and on a particular day that was actually considered very unlikely to occur after the discontinuation of posaconazole treatment, the CYP3A4 substrate drug can be administered. Since certain plasma levels may not be safe, in some embodiments, the method of the present invention administers the CYP3A4 substrate drug when at least one of the AUC, Cmax, or the GMR of AUC or Cmax of the CYP3A4 substrate drug is at or below the maximum level and greater than the predicted level (e.g., immediately upon such occurrence). In some embodiments, the maximum level is the plasma level of the CYP3A4 substrate drug at which the benefit of treating the patient with the CYP3A4 substrate drug outweighs the risk. Above the maximum level, the risk of treatment outweighs the benefit. Non-limiting examples of the maximum levels of various CYP3A4 substrate drugs are shown as "Target Safety Levels" in Table A.Because certain plasma levels can be unsafe, in some embodiments, if at least one of the actual AUC or Cmax of a CYP3A4 substrate drug is from 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 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% (including all ranges and sub-ranges thereof), the CYP3A4 substrate drug is administered.In some embodiments, after posaconazole discontinuation, if at least one of the GMRs of AUC or Cmax becomes from about 30-fold to about 1.05-fold of the baseline AUC or Cmax, for example, compared to each of the normal baseline values of such parameters, 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 9.8-fold, about 9.7-fold, about 9.6-fold, about 9.5-fold, about 9.4-fold, about 9.3-fold, about 9.2-fold, about 9.1-fold, about 9-fold, about 8.9-fold, about 8.8-fold, about 8.7-fold, about 8.6-fold, about 8.5-fold, about 8.4-fold, about 8.3-fold, about 8.2-fold, about 8.1-fold, about 8.0-fold, about 7.9-fold, about 7.8-fold, about 7.7-fold, about 7.6-fold, about 7.5-fold, about 7.4-fold, about 7.3-fold, about 7.2-fold, about 7.1-fold, about 7.0-fold, about 6.9-fold, about 6.8-fold, about 6.7-fold, about 6.6-fold, about 6.5-fold, about 6.4-fold, about 6.3-fold, about 6.2-fold, about 6.1-fold, about 6.0-fold, about 5.9-fold, about 5.8-fold, about 5.7-fold, about 5.6-fold, about 5.5-fold, about 5.4-fold, about 5.3-fold, about 5.2-fold, about 5.1-fold, about 5.0-fold, about 4.9-fold, about 4.8-fold, about 4.7-fold, about 4.6-fold, about 4.5-fold, about 4.4-fold, about 4.3-fold, about 4.2-fold, about 4.1-fold, about 4.0-fold, about 3.9-fold, about 3.8-fold, about 3.7-fold, about 3.6-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), a CYP3A4 substrate drug is administered. In some embodiments, the administration begins 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 posaconazole discontinuation.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 the normal baseline, which can be done 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 posaconazole discontinuation. As another example, in some embodiments, ranolazine is administered to provide an AUC of about 150% to about 105% of the normal baseline, which can be done 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 posaconazole discontinuation.

[0190]

[0192] In some embodiments, the method of the present invention requires that when a CYP3A4 substrate drug is administered, the plasma level of the substrate drug (i.e., at least one of AUC, Cmax, or the GMR of AUC or Cmax) does not exceed a specific maximum level (e.g., about 25%) by other methods. That is, in some embodiments, the maximum level determines when to administer the CYP3A4 substrate drug, and the CYP3A4 substrate drug is administered only when at least one of AUC, Cmax, or the GMR of AUC or Cmax is below the maximum level. In some embodiments, the maximum level is less than at least one of the AUC, Cmax, or the GMR of AUC or Cmax of the CYP3A4 substrate drug that occurs when the substrate drug is co-administered with posaconazole (see the co-administration levels of AUC and Cmax in Table A). In some embodiments, the maximum level is the plasma level at which the benefit of treating a patient with a CYP3A4 substrate drug outweighs the risk. In some embodiments, the maximum level is the target safety level provided in Table A. When a CYP3A4 substrate drug is administered and at least one of the AUC, Cmax, or the GMR level of AUC or Cmax exceeds the target safety level, the administration is delayed until at least one of the AUC, Cmax, or the GMR level of AUC or Cmax is below the target safety level.

[0191]

[0193] In some embodiments, the maximum level is related to the incidence of adverse events. In some embodiments, the incidence of adverse events establishing the 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%, at least about 50% in a population of patients receiving the same treatment. In some embodiments, the decision of whether to administer a CYP3A4 substrate drug is based on a risk / benefit analysis (e.g., as described above).

[0192]

[0194] When lurasidone is used as an example, an increase of about 300% in the AUC of lurasidone (an increase of about 3 times the GMR) is associated with drowsiness, and an increase of 400% in the AUC (or an increase of about 4 times the GMR) is associated with akathisia. For the benefit of treating patients, in some embodiments, lurasidone is administered when the AUC increases by a maximum of about 300% (an increase of about 3 times the GMR), but is not administered when the AUC increases by about 400% (an increase of about 4 times the GMR). In some embodiments, the maximum level of lurasidone is an increase of 216% in the baseline AUC. In some embodiments, for example, when the need for treating a patient exceeds the risk, the maximum level may be an increase of about 500% in the baseline AUC. In other embodiments, the maximum level can be any value in the range of less than 500% to 216% of the baseline AUC, including any range between these values. Thus, in some embodiments, the maximum level of lurasidone is 400%, about 300%, or about 216% of the normal baseline level of the AUC. Thus, in some embodiments, lurasidone is administered as soon as the AUC reaches about 400%, about 350%, about 300%, about 275%, about 250%, about 225%, about 216%, about 215%, about 210%, about 205%, about 200%, about 195%, about 190%, about 185%, about 180%, about 175%, about 170%, about 165%, about 160%, about 155%, about 150%, about 145%, about 140%, about 135%, about 130%, about 125%, about 120%, about 115%, about 110%, about 105% or less (including all values and ranges therebetween), 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, and 30 days after the discontinuation of posaconazole.

[0193]

[0195] In some embodiments, if at least one of the AUC or Cmax is greater than about 3000% of the normal baseline AUC of the CYP3A4 substrate drug (as defined above), for example, 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%, 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 sub - ranges thereof), the CYP3A4 substrate drug is not administered. In some embodiments, if at least one of the GMR of the AUC or Cmax is greater than about 30 - fold of the normal baseline AUC of the CYP3A4 substrate drug (as defined above), for example, 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 9.5 - 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 sub - ranges thereof), the CYP3A4 substrate drug is not administered.

[0194]

[0196] As contemplated herein, Applicants have found that the inhibitory effect of posaconazole on CYP3A4 persists substantially longer than predicted from its half-life. Thus, in some embodiments, the method provides for administering a CYP3A4 substrate drug as soon as sufficient posaconazole has been eliminated 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 an increase in the level 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, and thus, the delay period necessary to safely administer a CYP3A4 substrate drug after discontinuation of posaconazole may differ in these patient populations. Specifically, Applicants measured the elimination half-life of posaconazole in normal weight patients at 33.6 hours, whereas the elimination half-life of posaconazole in obese patients was measured at 58.3 hours. Table B shows the mean steady state concentrations of posaconazole measured in normal and obese patients in two separate clinical trials (BOW-001 and BOW-002) conducted by Applicants. In the two clinical studies, the same protocol was used to measure the elimination half-life of posaconazole, allowing the data for normal patients ("All Normal") and obese patients ("All Obese") from each study to be combined.

[0195]

Table 8

[0196]

[0198] In some embodiments, the CYP3A4 substrate drug is administered after at least about 2 half-lives of posaconazole have elapsed, such as 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 after a period exceeding that (including all values and sub-ranges therebetween).

[0197]

[0199] In some embodiments, the timing of administration of the CYP3A4 substrate drug is based on the posaconazole level measured by the applicant. In some embodiments, the CYP3A4 substrate drug is administered when the posaconazole level has decreased by at least about 50% of the steady-state level, such as 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 sub-ranges therebetween). In some embodiments, the CYP3A4 substrate drug is administered as soon as the posaconazole level reaches about 50% of the steady-state level, such as 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 sub-ranges therebetween).

[0198]

[0200] In some embodiments, the CYP3A4 substrate drug is administered as soon as the following two conditions are met: (i) the posaconazole level is reduced by at least about 50% of the steady-state level, such as 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 below the target level considered safe but exceeds the 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 safety level" disclosed in Table A for the CYP3A4 substrate drug.

[0199]

[0201] In some embodiments, the method provides for administering to a patient a reduced dose of a CYP3A4 substrate drug (as defined herein, compared to the reference dose). The reduced dose can be administered concurrently with posaconazole, the day after posaconazole is discontinued, or after any of the delay periods 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 posaconazole discontinuation). In some embodiments, the reduced dose is administered over a period of 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 comprises 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 the day that 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 prior to the day that the reduced dose provides an AUC that is less than 100% of the normal baseline, provided that the AUC does not exceed the safety level 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 set forth in Table A for the CYP3A4 substrate drug.

[0200]

[0202] For example, in some embodiments, the method of the present disclosure provides for administering a reduced dose of lurasidone that provides a maximum GMR of about 4.34 to 1 of the patient's normal baseline, and then administering a 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; then the patient discontinues treatment with posaconazole and, within 1 to 3 days after discontinuing posaconazole, begins administering a reduced dose of lurasidone (e.g., about 60 - 80 mg) for about 21 to 28 days; on a day within the range of about 21 to 28 days after discontinuing posaconazole, the patient begins administering a reference dose of 120 mg of lurasidone. Alternatively, in some embodiments, the patient may be administered 60 mg of lurasidone from about 9 days to about 12 days after discontinuing posaconazole, and then the patient begins administering a reference dose of 120 mg.

[0201]

[0203] In some embodiments, the reduced dose of CYP3A4 substrate drug is administered as soon as the posaconazole 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 sub - ranges therebetween).

[0202]

[0204] In some embodiments, a reduced dose of a CYP3A4 substrate drug is administered as soon as the following two conditions are met. (i) The posaconazole level is reduced by at least about 50% of the steady-state level, for example, 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 below a target level considered safe but above the 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 safety 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. In some embodiments, the standard dose for treating chronic angina ranges from 500 to 1000 mg. In some embodiments, the standard dose is administered twice a day. 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 240 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 sub-ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0204]

[0206] In an embodiment, the CYP3A4 substrate drug is lurasidone. In some embodiments, lurasidone is indicated for the treatment of schizophrenia in adults and adolescents (13 - 17 years old), type I bipolar disorder (bipolar depression) in adults, moderate bipolar depression, severe bipolar depression, and depressive episodes associated with severe bipolar depression with acute suicidal ideation and behavior (ASIB), as monotherapy or as adjunctive therapy with lithium or valproic acid. In some embodiments, the standard dose for treating schizophrenia in adults ranges from 40 to 160 mg per day (e.g., 40, 60, 80, 100, 120, 140, 160, or 180 mg). In some cases, the standard dose for treating schizophrenia in adolescents (13 - 17 years old) ranges from 48 to 80 mg (e.g., 40, 60, or 80 mg). In some embodiments, the standard dose for treating bipolar depression in adults ranges from 20 to 120 mg per day (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) ranges from 20 to 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 sub - ranges thereof), and treatment is postponed for at least about 2 - 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 - 42 days from the discontinuation of the posaconazole regimen.

[0205]

[0207] In embodiments where the CYP3A4 substrate drug is tadalafil, the daily dose of tadalafil 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 sub - ranges thereof), and treatment is postponed for at least 2 - 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 - 42 days from the discontinuation of the posaconazole regimen.

[0206]

[0208] In other embodiments where the CYP3A4 substrate drug is tadalafil, the dose of tadalafil 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 sub - ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the 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, for example, 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 sub - ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of 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, for example, 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 sub-ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0209]

[0211] In some embodiments, the CYP3A4 substrate drug is everolimus, and the daily dose of everolimus is about 10 mg or less, for example, 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 sub-ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0210]

[0212] In some embodiments, the CYP3A4 substrate drug is abemaciclib, and the daily dose of abemaciclib is about 400 mg or less, for example, 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 sub-ranges thereof), and treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0211]

[0213] In some embodiments, the CYP3A4 substrate drug is ibacaftool, and the daily dose of ibacaftool is about 300 mg or less, for example, 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0212]

[0214] In some embodiments, the CYP3A4 substrate drug is ruxolitinib or a pharmaceutically acceptable salt thereof (e.g., ruxolitinib phosphate), and the daily dose of ruxolitinib phosphate is about 50 mg or less, for example, 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the 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, for example, 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0214]

[0216] In some embodiments, the CYP3A4 substrate drug is ivacaftor / tezacaftor, and the daily dose of tezacaftor is about 100 mg or less, for example, 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 sub-ranges thereof), and the daily dose of ivacaftor is about 300 mg or less, for example, about 290 mg, about 280 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0215]

[0217] In some embodiments, the CYP3A4 substrate drug is regorafenib, and the daily dose of regorafenib is about 160 mg or less, for example, 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0216]

[0218] In some embodiments, the CYP3A4 substrate drug is daclatasvir, and the daily dose of daclatasvir is about 90 mg or less, for example, 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 sub-ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0217]

[0219] In some embodiments, the CYP3A4 substrate drug is crizotinib, and the daily dose of crizotinib is about 500 mg or less, for example, 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 sub - ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0218]

[0220] In some embodiments, the CYP3A4 substrate drug is naloxegol or a pharmaceutically acceptable salt thereof (e.g., naloxegol oxalate), and the daily dose of naloxegol oxalate is about 25 mg or less, for example, 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 sub - ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0219]

[0221] In some embodiments, the CYP3A4 substrate drug is dabrafenib, and the daily dose of dabrafenib is about 300 mg or less, for example, 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 sub - ranges thereof). Treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0220]

[0222] In some embodiments, the CYP3A4 substrate drugs are elbasvir and grazoprevir, the daily dose of elbasvir is about 1000 mg or less, for example, 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 sub-ranges thereof), the daily dose of grazoprevir is about 2000 mg or less, for example, 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 sub-ranges thereof), and the treatment is postponed for at least 2 to 42 days from the discontinuation of the posaconazole regimen, or the dose is reduced for about 2 to 42 days from the discontinuation of the posaconazole regimen.

[0221]

[0223] In addition to the previous embodiments, the following embodiments further illustrate methods of administering specific CYP3A4 substrate drugs of the present disclosure.

[0222]

[0224] In some embodiments, the CYP3A4 substrate drug is abemaciclib. The diseases or conditions treated with abemaciclib can include the diseases or conditions described herein, or the diseases or conditions 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 HR-positive, 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 can 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 HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine therapy, the standard dose is 150 mg, administered twice daily (total standard daily dose is 300 mg). When abemaciclib is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy, in combination with fulvestrant, the standard dose is 150 mg, administered twice daily (total standard daily dose is 300 mg). When 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, in combination with fulvestrant, the standard dose is 200 mg, administered twice daily (total standard daily dose is 400 mg).Accordingly, in various embodiments, the total daily reference 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, when the total daily reference dose of abemaciclib is, for example, 400 mg, the patient takes a reduced total daily dose of abemaciclib (concurrently with posaconazole or after a delay period following discontinuation of 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 total daily reference 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 total daily reference 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). When the total daily reference 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). When the total daily reference 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 daily reference total dose of abemaciclib is 200 mg, the reduced daily total 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 daily reference total dose of abemaciclib is 150 mg, the reduced daily total 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 daily reference total dose of abemaciclib is 100 mg, the reduced daily total dose of abemaciclib is, for example, 25 mg, 50 mg, or 75 mg (including all integers and ranges therebetween). Similarly, when 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). When 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 ado-trastuzumab emtansine. The disease or condition to be treated with ado-trastuzumab emtansine may include the diseases or conditions described herein, or the diseases or conditions for which ado-trastuzumab emtansine is indicated. For example, in some embodiments, ado-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 separately or in combination, and the patient must have received prior treatment for metastatic disease or have not developed disease recurrence during or within 6 months after completion of adjuvant therapy. Ado-trastuzumab emtansine can be administered via intravenous infusion in dosage forms of 2.4 mg / kg, 3 mg / kg, or 3.6 mg / kg. In some embodiments, ado-trastuzumab emtansine is administered once every 3 weeks up to a total dose of 3.6 mg every 3 weeks. For example, if ado-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 separately or in combination, and the patient must have received prior treatment for metastatic disease or have not developed disease recurrence during or within 6 months after completion of adjuvant therapy, the standard dose is 3.6 mg / kg every 3 weeks (standard total dose is 3.6 mg / kg every 3 weeks). Thus, in various embodiments, the standard total daily dose of ado-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 total daily dose of trastuzumab emtansine is, for example, 3.6 mg every three weeks, the patient takes the reduced total daily dose of trastuzumab emtansine (either concurrently with posaconazole or after a delay period following discontinuation of posaconazole). In some embodiments, the reduced total daily dose of trastuzumab emtansine is, for example, 0.3 mg / kg every three weeks, 0.6 mg / kg every three weeks, 0.9 mg / kg every three weeks, 1.2 mg / kg every three weeks, 1.5 mg / kg every three weeks, 1.8 mg / kg every three weeks, 2.1 mg / kg every three weeks, 2.4 mg / kg every three weeks, 2.7 mg / kg every three weeks, 3.0 mg / kg every three weeks, 3.3 mg / kg every three weeks (including all integers and ranges therebetween). When the total daily dose of trastuzumab emtansine is 3.6 mg / kg every three weeks, the reduced total daily reference dose of trastuzumab emtansine is, for example, 0.3 mg / kg every three weeks, 0.6 mg / kg every three weeks, 0.9 mg / kg every three weeks, 1.2 mg / kg every three weeks, 1.5 mg / kg every three weeks, 1.8 mg / kg every three weeks, 2.1 mg / kg every three weeks, 2.4 mg / kg every three weeks, 2.7 mg / kg every three weeks, 3.0 mg / kg every three weeks, 3.3 mg / kg every three weeks (including all integers and ranges therebetween). When the total daily dose of trastuzumab emtansine is 3.0 mg / kg every three weeks, the reduced total daily reference dose of trastuzumab emtansine is, for example, 0.3 mg / kg every three weeks, 0.6 mg / kg every three weeks, 0.9 mg / kg every three weeks, 1.2 mg / kg every three weeks, 1.5 mg / kg every three weeks, 1.8 mg / kg every three weeks, 2.1 mg / kg every three weeks, 2.4 mg / kg every three weeks, or 2.7 mg / kg every three weeks (including all integers and ranges therebetween).When the total daily dose of trastuzumab emtansine is 2.4 mg / kg every three weeks, the reference total daily dose of reduced trastuzumab emtansine is, for example, 0.3 mg / kg every three weeks, 0.6 mg / kg every three weeks, 0.9 mg / kg every three weeks, 1.2 mg / kg every three weeks, 1.5 mg / kg every three weeks, 1.8 mg / kg every three weeks, or 2.1 mg / kg every three 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 with apalutamide may include the diseases or conditions described herein, or the diseases or conditions 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 can be administered in a dosage form of 60 mg. In some embodiments, apalutamide is administered once daily up to a total daily dose of 240 mg. For example, when apalutamide is indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer, the standard dose is 240 mg and it is administered once daily (the standard total daily dose is 240 mg). Thus, in various embodiments, the standard total 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 total daily dose of apalutamide is, for example, 240 mg, the patient takes a reduced total daily dose of apalutamide (concurrently with posaconazole or after a delayed period following discontinuation of 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). When the standard 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). When the standard 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). When the standard 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, when the individual standard dose of apalutamide is 60 mg, the individual reduced standard dose of apalutamide is, for example, 30 mg.

[0225]

[0227] In some embodiments, the CYP3A4 substrate drug is aripiprazole (ABILIFY®). The diseases or conditions treated by aripiprazole may include the diseases or conditions described herein, or the diseases or conditions for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is orally indicated for schizophrenia. In some embodiments, aripiprazole is orally indicated for the acute treatment of manic and mixed episodes associated with bipolar I disorder. In some embodiments, aripiprazole is orally indicated for the adjunctive treatment of major depressive disorder. In some embodiments, aripiprazole is orally indicated for hypersensitivity associated with autistic disorder. In some embodiments, aripiprazole is orally indicated for the treatment of Tourette's disorder. In some embodiments, aripiprazole is indicated for intramuscular injection for agitation associated with schizophrenia or bipolar mania. Aripiprazole may be administered in tablet dosage forms of 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg, or orally disintegrating tablets of 10 mg or 15 mg, or an oral solution of 1 mg / mL, or a single-dose vial of 9.75 mg / 1.3 mL. In some embodiments, aripiprazole is administered up to a total daily dose of 30 mg (oral or by injection) once daily. For example, when aripiprazole is indicated for adult schizophrenia, the initial reference dose is 10 - 15 mg, administered once daily (the reference total daily dose is 10 - 15 mg). When aripiprazole is indicated for adult schizophrenia, the recommended reference dose is 10 - 15 mg, administered once daily (the reference total daily dose is 10 - 15 mg). When aripiprazole is indicated for adult schizophrenia, the maximum reference dose is 30 mg, administered once daily (the reference total daily dose is 30 mg). For example, when aripiprazole is indicated for adolescent schizophrenia, the initial reference dose is 2 mg, administered once daily (the reference total daily dose is 2 mg). When aripiprazole is indicated for adolescent schizophrenia, the recommended reference dose is 10 mg, administered once daily (the reference total daily dose is 10 mg).When aripiprazole is indicated for schizophrenia in adolescents, the maximum standard dose is 30 mg, administered once daily (total daily standard dose is 30 mg). For example, when aripiprazole is indicated for bipolar mania in adults (monotherapy), the initial standard dose is 15 mg, administered once daily (total daily standard dose is 15 mg). When aripiprazole is indicated for bipolar mania in adults (monotherapy), the recommended standard dose is 15 mg, administered once daily (total daily standard dose is 15 mg). When aripiprazole is indicated for bipolar mania in adults (monotherapy), the maximum standard dose is 30 mg, administered once daily (total daily standard dose is 30 mg). For example, when aripiprazole is indicated for bipolar mania in adults (adjunct to lithium or valproic acid), the initial standard dose is 10 - 15 mg, administered once daily (total daily standard dose is 10 - 15 mg). When aripiprazole is indicated for bipolar mania in adults (adjunct to lithium or valproic acid), the recommended standard dose is 15 mg, administered once daily (total daily standard dose is 15 mg). When aripiprazole is indicated for bipolar mania in adults (adjunct to lithium or valproic acid), the maximum standard dose is 30 mg, administered once daily (total daily standard dose is 30 mg). For example, when aripiprazole is indicated for bipolar mania in children (monotherapy or adjunct to lithium or valproic acid), the initial standard dose is 2 mg, administered once daily (total daily standard dose is 2 mg). When aripiprazole is indicated for bipolar mania in children (monotherapy or adjunct to lithium or valproic acid), the recommended standard dose is 10 mg, administered once daily (total daily standard dose is 10 mg). When aripiprazole is indicated for bipolar mania in children (monotherapy or adjunct to lithium or valproic acid), the maximum standard dose is 30 mg, administered once daily (total daily standard dose is 30 mg). For example, when aripiprazole is indicated for major depressive disorder in adults (adjunct to antidepressants), the initial standard dose is 2 - 5 mg, administered once daily (total daily standard dose is 2 - 5 mg).When aripiprazole is indicated for major depressive disorder in adults (as an adjunct to antidepressants), the recommended standard dose is 5 - 10 mg, administered once daily (total daily standard dose is 5 - 10 mg). When aripiprazole is indicated for major depressive disorder in adults (as an adjunct to antidepressants), the maximum standard dose is 15 mg, administered once daily (total daily standard dose is 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 standard dose is 2 mg). When aripiprazole is indicated for hypersensitivity associated with autistic disorder in pediatric patients, the recommended standard dose is 5 - 10 mg, administered once daily (total daily standard dose is 5 - 10 mg). When aripiprazole is indicated for hypersensitivity associated with autistic disorder in pediatric patients, the maximum standard dose is 15 mg, administered once daily (total daily standard dose is 15 mg). For example, when aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the initial standard dose is 2 mg, administered once daily (total daily standard dose is 2 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the recommended standard dose is 5 mg, administered once daily (total daily standard dose is 5 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing less than 50 kg, the maximum standard dose is 10 mg, administered once daily (total daily standard dose is 10 mg). For example, when aripiprazole is indicated for Tourette's disorder in patients weighing 50 kg or more, the initial standard dose is 2 mg, administered once daily (total daily standard dose is 2 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing 50 kg or more, the recommended standard dose is 10 mg, administered once daily (total daily standard dose is 10 mg). When aripiprazole is indicated for Tourette's disorder in patients weighing 50 kg or more, the maximum standard dose is 20 mg, administered once daily (total daily standard dose is 20 mg). For example, when aripiprazole is indicated 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 daily standard dose is 9.75 mg / 1.3 mL).When aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania in adults, the maximum standard dose is 30 mg, administered intramuscularly once daily (total standard daily dose is 30 mg). Thus, in various embodiments, the total standard daily 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 standard daily dose of aripiprazole is, for example, 30 mg, the patient takes a reduced total daily dose of aripiprazole (concurrently with posaconazole or after a delay period following discontinuation of 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). When the total standard daily dose of aripiprazole is 30 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, 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 total standard daily 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 total daily reference dose of aripiprazole is 15 mg, the total daily dose of the reduced 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). When the total daily reference dose of aripiprazole is 10 mg, the total daily dose of the reduced 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 total daily reference dose of aripiprazole is 5 mg, the total daily dose of the reduced aripiprazole is, for example, 1 mg, 2 mg, 3 mg, or 4 mg (including all integers and ranges therebetween). When the total daily reference dose of aripiprazole is 2 mg, the total daily dose of the reduced aripiprazole is, for example, 1 mg. Similarly, when the individual reference dose of aripiprazole is 30 mg, the individual reference dose of the reduced 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 individual reference dose of the reduced 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 individual reference dose of the reduced 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 individual reference dose of the reduced aripiprazole is, for example, 1 mg, 2 mg, 3 mg, or 4 mg (including all integers and ranges therebetween).When the individual reference dose of aripiprazole is 2 mg, the individual reference dose of the reduced aripiprazole is, for example, 1 mg.

[0226]

[0228] In some embodiments, the CYP3A4 substrate drug is aripiprazole (ARISTADA®). The diseases or conditions treated with aripiprazole may include the diseases or conditions described herein, or the diseases or conditions for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is indicated for schizophrenia. Aripiprazole can be administered in a single-use prefilled syringe in tablet dosage forms 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 6 weeks at a maximum total dose of 882 mg. In some embodiments, aripiprazole is administered once every 2 months at a maximum total dose of 1064 mg. For example, when aripiprazole is indicated for schizophrenia, the reference dose is 441 mg, 662 mg, or 882 mg administered once a month, 882 mg administered once every 6 weeks, or 1064 mg administered once every 2 months (reference total doses are 441 mg per month, 662 mg per month, 882 mg per month, 882 mg every 6 weeks, or 1064 mg every 2 months). Thus, in various embodiments, the reference total dose of aripiprazole can be, for example, 441 mg per month, 662 mg per month, 882 mg per month, 882 mg every 6 weeks, or 1064 mg every 2 months. According to certain embodiments of the present disclosure, when the reference total daily dose of aripiprazole is, for example, 1064 mg every 2 months, the patient takes a reduced total daily dose of aripiprazole (either concurrently with posaconazole or after a delay period following discontinuation of 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, 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); or, 10 mg every 6 weeks, 20 mg every 6 weeks, 30 mg every 6 weeks, 40 mg every 6 weeks, 50 mg every 6 weeks, 60 mg every 6 weeks, 70 mg every 6 weeks, 80 mg every 6 weeks, 90 mg every 6 weeks, 100 mg every 6 weeks, 120 mg every 6 weeks, 140 mg every 6 weeks, 160 mg every 6 weeks, 180 mg every 6 weeks, 200 mg every 6 weeks, 220 mg every 6 weeks, 240 mg every 6 weeks, 260 mg every 6 weeks, 280 mg every 6 weeks, 300 mg every 6 weeks, 320 mg every 6 weeks, 340 mg every 6 weeks, 360 mg every 6 weeks, 380 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); or, 10 mg every 2 months, 20 mg every 2 months, 30 mg every 2 months, 40 mg every 2 months, 50 mg every 2 months, 60 mg every 2 months, 70 mg every 2 months, 80 mg every 2 months, 90 mg every 2 months, 100 mg every 2 months, 120 mg every 2 months, 140 mg every 2 months, 160 mg every 2 months, 180 mg every 2 months, 200 mg every 2 months, 220 mg every 2 months, 240 mg every 2 months, 260 mg every 2 months, 280 mg every 2 months, 300 mg every 2 months, 320 mg every 2 months,340 mg every two months, 360 mg every two months, 380 mg every two months, 400 mg every two months, 420 mg every two months, 440 mg every two months, 460 mg every two months, 480 mg every two months, 500 mg every two months, 520 mg every two months, 540 mg every two months, 560 mg every two months, 580 mg every two months, 600 mg every two months, 620 mg every two months, 640 mg every two months, 660 mg every two months, 680 mg every two months, 700 mg every two months, 720 mg every two months, 740 mg every two months, 760 mg every two months, 780 mg every two months, 800 mg every two months, 820 mg every two months, 840 mg every two months, 860 mg every two months, 880 mg every two months, 900 mg every two months, 920 mg every two months, 940 mg every two months, 960 mg every two months, 180 mg every two months, 200 mg every two months, 220 mg every two months, 240 mg every two months, 960 mg every two months, 980 mg every two months, 1000 mg every two months, 1020 mg every two months, 1040 mg every two months, or 1060 mg every two months (including all integers and ranges therebetween). If the reference total dose of aripiprazole is 1064 mg every two months, the total dose of reduced aripiprazole is, for example, 10 mg every two months, 20 mg every two months, 30 mg every two months, 40 mg every two months, 50 mg every two months, 60 mg every two months, 70 mg every two months, 80 mg every two months, 90 mg every two months, 100 mg every two months, 120 mg every two months, 140 mg every two months, 160 mg every two months, 180 mg every two months, 200 mg every two months, 220 mg every two months, 240 mg every two months, 260 mg every two months, 280 mg every two months, 300 mg every two months, 320 mg every two months, 340 mg every two months, 360 mg every two months, 380 mg every two months, 400 mg every two months, 420 mg every two months, 440 mg every two months, 460 mg every two months, 480 mg every two months, 500 mg every two months, 520 mg every two months, 540 mg every two months, 560 mg every two months, 580 mg every two months, 600 mg every two months, 620 mg every two months, 640 mg every two months, 660 mg every two months, 680 mg every two months, 700 mg every two months, 720 mg every two months, 740 mg every two months, 760 mg every two months, 780 mg every two months, 800 mg every two months, 820 mg every two months, 840 mg every two months, 860 mg every two months, 880 mg every two months, 900 mg every two 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 reference total dose of aripiprazole is 882 mg in 6 weeks, the total dose of reduced aripiprazole is, for example, 10 mg in 6 weeks, 20 mg in 6 weeks, 30 mg in 6 weeks, 40 mg in 6 weeks, 50 mg in 6 weeks, 60 mg in 6 weeks, 70 mg in 6 weeks, 80 mg in 6 weeks, 90 mg in 6 weeks, 100 mg in 6 weeks, 120 mg in 6 weeks, 140 mg in 6 weeks, 160 mg in 6 weeks, 180 mg in 6 weeks, 200 mg in 6 weeks, 220 mg in 6 weeks, 240 mg in 6 weeks, 260 mg in 6 weeks, 280 mg in 6 weeks, 300 mg in 6 weeks, 320 mg in 6 weeks, 340 mg in 6 weeks, 360 mg in 6 weeks, 380 mg in 6 weeks, 400 mg in 6 weeks, 420 mg in 6 weeks, 440 mg in 6 weeks, 460 mg in 6 weeks, 480 mg in 6 weeks, 500 mg in 6 weeks, 520 mg in 6 weeks, 540 mg in 6 weeks, 560 mg in 6 weeks, 580 mg in 6 weeks, 600 mg in 6 weeks, 620 mg in 6 weeks, 640 mg in 6 weeks, 660 mg in 6 weeks, 680 mg in 6 weeks, 700 mg in 6 weeks, 720 mg in 6 weeks, 740 mg in 6 weeks, 760 mg in 6 weeks, 780 mg in 6 weeks, 800 mg in 6 weeks, 820 mg in 6 weeks, 840 mg in 6 weeks, 860 mg in 6 weeks, or 880 mg in 6 weeks (including all integers and ranges therebetween). If the reference total dose of aripiprazole is 882 mg in 1 month, the total dose of reduced aripiprazole is, for example, 10 mg in 1 month, 20 mg in 1 month, 30 mg in 1 month, 40 mg in 1 month, 50 mg in 1 month, 60 mg in 1 month, 70 mg in 1 month, 80 mg in 1 month, 90 mg in 1 month, 100 mg in 1 month, 120 mg in 1 month, 140 mg in 1 month, 160 mg in 1 month, 180 mg in 1 month, 200 mg in 1 month, 220 mg in 1 month, 240 mg in 1 month, 260 mg in 1 month, 280 mg in 1 month, 300 mg in 1 month, 320 mg in 1 month, 340 mg in 1 month, 360 mg in 1 month, 380 mg in 1 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). When the standard total dose of aripiprazole is 662 mg per month, the total dose of the reduced 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, 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, or 660 mg per month (including all integers and ranges therebetween). When the standard total dose of aripiprazole is 441 mg per month, the total dose of the reduced 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,It is 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®). The diseases or conditions treated with aripiprazole may include the diseases or conditions described herein, or the diseases or conditions for which aripiprazole is indicated. For example, in some embodiments, aripiprazole is indicated for the treatment of adult schizophrenia. In some embodiments, aripiprazole is indicated as a maintenance monotherapy treatment for adult type I bipolar disorder. Aripiprazole can be administered by injection at 160, 200 mg, 300 mg, or 400 mg. 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 adult schizophrenia, the reference dose is 400 mg and is administered once a month (total reference daily dose is 400 mg per month). For example, when aripiprazole is indicated as a maintenance monotherapy treatment for adult type I bipolar disorder, the reference dose is 400 mg and is administered once a month (total reference daily dose is 400 mg per month). Thus, in various embodiments, the total reference 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, when the total reference daily dose of aripiprazole is, for example, 400 mg per month, the patient takes a reduced total daily dose of aripiprazole (simultaneously with posaconazole or after a delayed period following discontinuation of posaconazole).In some embodiments, the reduced total dosage 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, or 390 mg per month. When the reference total dosage of aripiprazole is 400 mg per month, the reduced total dosage of aripiprazole is 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, or 390 mg per month (including all integers and ranges therebetween).When 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, or 290 mg per month (including all integers and ranges therebetween). When the standard total dose of aripiprazole is 200 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, or 190 mg per month (including all integers and ranges therebetween). When the standard total dose of aripiprazole is 160 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, 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. The diseases or conditions treated with bosutinib may include the diseases or conditions described herein, or the diseases or conditions 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 blast phase Ph+CML with resistance or intolerance to prior therapy. Bosutinib may 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 (total standard daily dose is 400 mg). For example, when bosutinib is indicated for chronic phase, accelerated phase, or blast phase Ph+CML with resistance or intolerance to prior therapy, the standard dose is 500 mg, administered once daily (total standard daily dose is 500 mg). In some embodiments, in patients who do not achieve a complete hematologic, cytogenetic, or molecular response and do not have grade 3 or greater adverse reactions, the dose is escalated in 100 mg increments once daily up to a maximum of 600 mg per day. Thus, in various embodiments, the total standard 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, when the total standard daily dose of bosutinib is, for example, 600 mg, the patient takes a reduced total daily dose of bosutinib (concurrently with posaconazole or after a delayed period following discontinuation of 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).When the total daily dose of bosutinib is 600 mg, the total daily dose of reduced 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). When the total daily dose of bosutinib is 500 mg, the total daily dose of reduced 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). When the total daily dose of bosutinib is 400 mg, the total daily dose of reduced 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, when the individual reference dose of bosutinib is 500 mg, the individual reference dose of reduced 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). When the individual reference dose of bosutinib is 400 mg, the individual reference dose of reduced 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 diseases or conditions treated by brexpiprazole may include the diseases or conditions described herein, or the diseases or conditions 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 can 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 (the reference total daily 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 reference dose is 2 mg, administered once daily (the reference total daily dose is 2 mg). When brexpiprazole is indicated for use as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), the maximum reference dose is 3 mg, administered once daily (the reference total daily dose is 3 mg). For example, when brexpiprazole is indicated for the treatment of schizophrenia, the starting reference dose is 1 mg, administered once daily (the reference total daily dose is 1 mg). When brexpiprazole is indicated for the treatment of schizophrenia, the recommended reference dose is 2 - 4 mg (e.g., 2 mg, 3 mg, or 4 mg), administered once daily (the reference total daily dose is 2 - 4 mg). When brexpiprazole is indicated for the treatment of schizophrenia, the maximum dose is 4 mg, administered once daily (the reference total daily dose is 4 mg).Accordingly, in various embodiments, the total daily reference dose of brexpiprazole can be, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg or 8 mg. According to certain embodiments of the present disclosure, when the total daily reference dose of brexpiprazole is, for example, 8 mg, the patient takes a reduced total daily dose of brexpiprazole (either concurrently with posaconazole or after a delayed period following discontinuation of posaconazole). In some embodiments, the reduced total daily dose of brexpiprazole is 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, or 7.75 mg. When the total daily reference dose of brexpiprazole is 6 mg, the reduced total daily dose of brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, or 5.75 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 4 mg, the reduced total daily dose of brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, or 3.75 mg (including all integers and ranges therebetween).When the total daily reference dose of brexpiprazole is 3 mg, the total daily dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, or 2.75 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 2 mg, the total daily dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, or 1.75 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 1 mg, the total daily dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, or 0.75 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 0.75 mg, the total daily dose of reduced brexpiprazole is, for example, 0.25 mg or 0.5 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 0.5 mg, the total daily dose of reduced brexpiprazole is, for example, 0.125 mg or 0.25 mg (including all integers and ranges therebetween). When the total daily reference dose of brexpiprazole is 0.25 mg, the total daily dose of reduced brexpiprazole is, for example, 0.125 mg. Similarly, when the individual reference dose of brexpiprazole is 4 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, or 3.75 mg (including all integers and ranges therebetween). When the individual reference dose of brexpiprazole is 3 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, or 2.75 mg (including all integers and ranges therebetween).When the individual reference dose of brexpiprazole is 2 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, or 1.75 mg (including all integers and ranges therebetween). When the individual reference dose of brexpiprazole is 1 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.25 mg, 0.5 mg, or 0.75 mg (including all integers and ranges therebetween). When the individual reference dose of brexpiprazole is 0.75 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.25 mg or 0.5 mg (including all integers and ranges therebetween). When the individual reference dose of brexpiprazole is 0.5 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.125 mg or 0.25 mg (including all integers and ranges therebetween). When the individual reference dose of brexpiprazole is 0.25 mg, the individual reference dose of reduced brexpiprazole is, for example, 0.125 mg.

[0230]

[0232] In some embodiments, the CYP3A4 substrate drug is brigatinib. The diseases or conditions treated with brigatinib may include the diseases or conditions described herein, or the diseases or conditions for which brigatinib is indicated. For example, in some embodiments, brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who are progressing on or intolerant to crizotinib. Brigatinib can be administered in dosage forms of 30 mg or 90 mg. In some embodiments, brigatinib is administered once daily up to a total daily dose of 180 mg. For example, when brigatinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who are progressing on or intolerant to crizotinib, the reference dose is 90 mg, administered once daily for the first 7 days, and increased to 180 mg once daily if tolerated (total daily reference dose is 90 mg or 180 mg). Thus, in various embodiments, the total daily reference dose of brigatinib can be, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 105 mg, 120 mg, 135 mg, 150 mg, 165 mg, or 180 mg. According to certain embodiments of the present disclosure, when the total daily reference dose of brigatinib is, for example, 180 mg, the patient takes a reduced total daily dose of brigatinib (concurrently with posaconazole or after a delay period after discontinuation of posaconazole). In some embodiments, the reduced total daily dose of brigatinib is, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 105 mg, 120 mg, 135 mg, 150 mg, or 165 mg (including all integers and ranges therebetween). When the total daily reference dose of brigatinib is 180 mg, the reduced total daily dose of brigatinib is, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 105 mg, 120 mg, 135 mg, 150 mg, 165 mg (including all integers and ranges therebetween).When the total daily reference dose of brigatinib is 120 mg, the total daily dose of reduced brigatinib can be, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, or 105 mg (including all integers and ranges therebetween). When the total daily reference dose of brigatinib is 90 mg, the total daily dose of reduced brigatinib can be, for example, 15 mg, 30 mg, 45 mg, 60 mg, or 75 mg (including all integers and ranges therebetween). When the total daily reference dose of brigatinib is 60 mg, the total daily dose of reduced brigatinib can be, for example, 15 mg, 30 mg, or 45 mg (including all integers and ranges therebetween). When the total daily reference dose of brigatinib is 30 mg, the total daily dose of reduced brigatinib can be, for example, 7.5 mg or 15 mg (including all integers and ranges therebetween). Similarly, when the individual reference dose of brigatinib is 90 mg, the individual reference dose of reduced brigatinib can be, for example, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg (including all integers and ranges therebetween). When the individual reference dose of brigatinib is 30 mg, the individual reference dose of reduced brigatinib can be, for example, 7.5 mg or 15 mg (including all integers and ranges therebetween).

[0231]

[0233] In some embodiments, the CYP3A4 substrate drug is cabazitaxel. The disease or condition treated with cabazitaxel can include the diseases or conditions described herein, or the diseases or conditions for which cabazitaxel is indicated. For example, in some embodiments, cabazitaxel is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have been treated with a treatment regimen containing docetaxel previously. Cabazitaxel can be administered by injection in a dosage form of 15 mg / m 2 , 20 mg / m 2 , or 25 mg / m 2 (sold as a single-dose vial of 60 mg / 1.5 mL). In some embodiments, cabazitaxel is administered once every three weeks, up to 25 mg / m 2It is administered according to the total dose. For example, cabazitaxel is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have been treated with a treatment regimen containing docetaxel previously. The reference dose is 20 mg / m 2 and is administered once every three weeks (the reference total dose is 20 mg / m 2 every three weeks). Accordingly, in various embodiments, the reference total dose of cabazitaxel is, for example, 2.5 mg / m 2 every three weeks, 5 mg / m 2 every three weeks, 7.5 mg / m 2 every three weeks, 10 mg / m 2 every three weeks, 12.5 mg / m 2 every three weeks, 15 mg / m 2 every three weeks, 17.5 mg / m 2 every three weeks, 20 mg / m 2 every three...

Claims

A pharmaceutical composition comprising encorafenib for use in a method of treating unresectable or metastatic cancer associated with BRAF V600E or V600K mutation in a patient, wherein the patient has been treated with posaconazole, and the method comprises: (a) discontinuing posaconazole treatment; (b) delaying the once-daily administration of 450 mg of encorafenib for at least 7 days after discontinuing posaconazole in step (a); then (c) administering 450 mg of encorafenib once daily; A pharmaceutical composition comprising the above. The pharmaceutical composition according to claim 1, wherein the patient is not obese. The pharmaceutical composition according to claim 1, wherein the patient has at least one of the following characteristics: i) a BMI of at least about 35; ii) a waist size exceeding about 42 inches; iii) a body fat percentage exceeding about 40%; iv) a total body fat exceeding about 40 kg; and v) being medically diagnosed as obese The pharmaceutical composition according to claim 1, which is selected from the group consisting of the above. The pharmaceutical composition according to claim 1, wherein 100 mg to 300 mg of encorafenib is administered concomitantly with posaconazole prior to the patient discontinuing posaconazole in step (a). The pharmaceutical composition according to claim 4, wherein the patient is administered 100 mg of encorafenib. The pharmaceutical composition according to claim 4, wherein the patient is administered 150 mg of encorafenib. The pharmaceutical composition according to claim 4, wherein the patient is administered 200 mg of encorafenib. The pharmaceutical composition according to claim 4, wherein the patient is administered 300 mg of encorafenib. The pharmaceutical composition according to claim 1, wherein 150 mg of encorafenib is administered concomitantly with posaconazole prior to the patient discontinuing posaconazole in step (a). The pharmaceutical composition according to claim 4, wherein 100 mg to 300 mg of encorafenib is administered to the patient from the time of discontinuing posaconazole treatment in step (a) until the pharmaceutical composition containing 450 mg of encorafenib is administered once daily in step (c). The pharmaceutical composition according to claim 10, wherein the patient is administered 100 mg of encorafenib from after step (a) until step (c).

12. The pharmaceutical composition according to claim 10, wherein the patient is administered 150 mg of encorafenib from after step (a) until step (c).

13. The pharmaceutical composition according to claim 10, wherein the patient is administered 200 mg of encorafenib from after step (a) until step (c).

14. The pharmaceutical composition according to claim 10, wherein 300 mg of encorafenib is administered to the patient simultaneously with posaconazole prior to discontinuation of posaconazole in step (a).

15. The pharmaceutical composition according to claim 1, wherein the administration in step (c) is 7 to 13 days after discontinuation of posaconazole in step (a).

16. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 7 days after discontinuation of posaconazole in step (a).

17. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 8 days after discontinuation of posaconazole in step (a).

18. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 9 days after discontinuation of posaconazole in step (a).

19. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 10 days after discontinuation of posaconazole in step (a).

20. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 11 days after discontinuation of posaconazole in step (a).

21. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 12 days after discontinuation of posaconazole in step (a).

22. The pharmaceutical composition according to claim 15, wherein the administration in step (c) is 13 days after discontinuation of posaconazole in step (a).

23. The pharmaceutical composition according to claim 3, wherein the patient has a BMI of at least about 35.

24. The pharmaceutical composition according to claim 3, wherein the patient has a waist size greater than about 42 inches.

25. The pharmaceutical composition according to claim 3, wherein the patient has a body fat percentage greater than about 40%.

26. The pharmaceutical composition according to claim 3, wherein the patient has a total body fat greater than about 40 kg.

27. The pharmaceutical composition according to claim 3, wherein the patient is diagnosed as medically obese. The pharmaceutical composition according to claim 1, wherein the method is to treat adult patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The pharmaceutical composition according to claim 1, wherein the method is to treat adult patients with metastatic non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (CRC) with BRAF V600E mutations.

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