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Methods of treatment with cyp3a4 substrate drugs

a technology of cyp3a4 and substrate drugs, which is applied in the direction of drug compositions, cardiovascular disorders, dispersed delivery, etc., can solve the problems that cyp3a4 substrate drugs cannot always be safely administered immediately after a patient has stopped posaconazole treatment, and can have serious and potentially life-threatening side effects

Pending Publication Date: 2022-05-12
BOW RIVER LLC
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Benefits of technology

[0007]Applicants have discovered that although CYP3A4 substrate drugs are generally only contraindicated for coadministration with strong CYP3A4 inhibitors, such as posaconazole, CYP3A4 substrate drugs cannot always be safely administered immediately after a patient has stopped posaconazole treatment. Applicants have discovered that posaconazole accumulation in the body of patients, particularly for specific patient populations as described herein, can result in serious and potentially life-threatening side effects if a CYP3A4 substrate drug is administered too soon, subsequent to the cessation of a posaconazole regimen. Accordingly, for CYP3A4 substrate drugs, particularly those contraindicated for coadministration with a strong CYP3A4 inhibitor (including but not limited to posaconazole), a washout or delay period of about 2-42 days (e.g., 2-21 days) between ceasing administration of the posaconazole regimen and starting administration of the CYP3A4 substrate drug is required in order to avoid or reduce the incidence of side effects resulting from administration of the CYP3A4 substrate drug. Alternatively, rather than delaying administering the CYP3A4 substrate drug after ceasing administration of the posaconazole regimen, in some embodiments, the Applicants have discovered that patients can safely be administered a reduced dose of the CYP3A4 substrate drug (reduced relative to the recommended dose of the CYP3A4 substrate drug) for a period of time (about 2-42 days (e.g., 2-21 days)) following cessation of the posaconazole regimen, after which the dose of the CYP3A4 substrate drug can be safely increased to the recommended level.

Problems solved by technology

Applicants have discovered that although CYP3A4 substrate drugs are generally only contraindicated for coadministration with strong CYP3A4 inhibitors, such as posaconazole, CYP3A4 substrate drugs cannot always be safely administered immediately after a patient has stopped posaconazole treatment.
Applicants have discovered that posaconazole accumulation in the body of patients, particularly for specific patient populations as described herein, can result in serious and potentially life-threatening side effects if a CYP3A4 substrate drug is administered too soon, subsequent to the cessation of a posaconazole regimen.

Method used

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embodiments i

[0274]1. A method of treating a patient who has previously been administered a therapeutically effective regimen of posaconazole, with a CYP3A4 substrate drug contraindicated for concomitant administration with a strong CYP3A4 inhibitor, said method comprising:

[0275]first treating the patient, or prescribing a first treatment to begin, with the CYP3A4 substrate drug at least 2-42 days after stopping administration of posaconazole.

[0276]2. The method of embodiment 1, wherein said CYP3A4 substrate drug is selected from the group consisting of lurasidone, ranolazine, lumacaftor / ivacaftor, venetoclax, trabectedin, ribociclib succinate, deflazacort, cinacalcet hydrochloride, pimavanserin tartrate, aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium, everolimus, saxagliptin hydrochloride, saxagliptin / metformin hydrochloride, ticagrelor, vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloride monohydrate, dronedarone hydroch...

example 1

inetic Studies with Posaconazole and Lurasidone

[0553]Inventors studied 6 obese male and female subjects (ages 18-50, BMI>35) taking Posaconazole oral tablets (300 mg qd) and Lurasidone (20 mg qd). Body weights and BMI measurements for the 6 subjects are provided below in Table 1.

TABLE 1Subject DemographicsSubject #Weight (kg)BMI (kg / m2)101-001111.845101-002136.844.4101-005137.751.2101-007103.736.8101-008122.339.8101-010120.043.9

[0554]Subjects were dosed with Lurasidone alone on Day 1, then subsequently dosed to steady-state Posaconazole levels, with a loading dose of 300 mg twice a day on Day 2 and 300 mg once a day thereafter over a period of 14 days. Posaconazole administration was then stopped and Lurasidone (20 mg qd) administered 2, 4, and 6 days after administration had ceased (studies days 17, 19, and 21 respectively). Lurasidone AUC was measured for 24 hours after each administration. Table 2 shows subject Lurasidone AUC levels 2, 4 and 6 days after Posaconazole was stopped,...

example 2

Impairment of Lurasidone Clearance after Discontinuation of Posaconazole, Impact of Obesity, and Implications for Patient Safety

[0560]The following studies were reported by Greenblatt et al., J. Clin. Psychopharmacol., 2018; 38(4):289-295 (doi: 10.1097 / JCP.0000000000000892), which is herein incorporated by reference in its entirety for all purposes.

[0561]The antipsychotic agent lurasidone is metabolized by Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such as ketoconazole, posaconazole, and ritonavir) is contraindicated due to the risk of sedation and movement disorders from high levels of lurasidone. This study evaluated the time-course of recovery from the posaconazole drug interaction, and the effect of obesity on the recovery process.

[0562]With posaconazole coadministration, lurasidone area under the concentration curve (AUC) increased by an arithmetic mean factor of 6.2 in normals, and by 4.9 in obese subjects. Post-treatment washout of posa...

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Abstract

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug, wherein the patient is treated with posaconazole. In some embodiments, the patient stops posaconazole treatment, waits for at least 2 days, and then is treated with the CYP3A4 substrate drug as soon as it is safe to do so. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 2-42 days after stopping posaconazole. In some embodiments, the patient is treated with a reduced dose of the CYP3A4 substrate drug for about 2-42 days.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 17 / 099,298, filed Nov. 16, 2020, now U.S. Pat. No. 11,123,346, which is a divisional of U.S. application Ser. No. 16 / 191,351, filed Nov. 14, 2018, now U.S. Pat. No. 10,835,529, which is a continuation-in-part of U.S. application Ser. No. 15 / 596,585, filed May 16, 2017, now U.S. Pat. No. 10,376,507, the entire contents of which are incorporated by reference in their entireties.BACKGROUND[0002]Posaconazole, also called Noxafil and Posanol, is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy, for the treatment of oropharyngeal candidiasis (OPC), including OPC refractor...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496
CPCA61K31/496A61P9/00A61P25/24A61P35/02A61P35/04A61K9/0019A61K9/0056A61K9/0078A61K9/0095A61K9/08A61K9/10A61K9/2004A61K9/4841A61P25/16A61P25/18A61K31/635A61K9/0053A61K31/00A61K31/397A61K31/407A61K31/4468A61K31/454A61K31/4745A61K31/497A61K31/498A61K31/4995A61K31/506A61K31/519A61K31/5383A61K31/5395A61K31/502
Inventor SRINIVASAN, SUNDARCHOW, CHRISTINA
Owner BOW RIVER LLC
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