Journal Article

Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments

DiNardo, Courtney D., Dunbar, Martin, Salem, Ahmed Hamed, Humerickhouse, Rod A., Wong, Shekman L., Kantarjian, Hagop M., Agarwal, Suresh K., Menon, Rajeev M., Konopleva, Marina Y., Potluri, Jalaja

2017

Overview

The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: ABT-199/GDC-0199 / Administration, Oral / Adult / Antifungal Agents - pharmacology / Antifungal Agents - therapeutic use / BCL-2 / Bridged Bicyclo Compounds, Heterocyclic - administration & dosage / Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics / CYP3A / Cytochrome P-450 CYP3A - metabolism / Drug dosages / FDA approval / Female / Fungal infections / Humans / Internal Medicine / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Lymphoma / Male / Middle Aged / Pharmaceutical industry / pharmacokinetic interaction / posaconazole / Quality / Research funding / Studies / Sulfonamides - administration & dosage / Sulfonamides - pharmacokinetics / Triazoles - administration & dosage / Triazoles - pharmacology / Tumors / venetoclax