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

Purpose: 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. Methods: Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m(2) 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. Findings: Compared with a venetoclax dose of 400 mg when administered alone (day 20), coad-ministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax C-max and AUC(0-24) by 53% and 76%, respectively, whereas coad-ministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC(0-24) by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC(0-24) by 7.1 and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. (C) 2017 Elsevier HS Journals, Inc. All rights reserved.