Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL‐2 Inhibitor: Results of a Single‐ and Multiple‐Dose Study

Authors:
Publisher website
Google Scholar
Abstract
Venetoclax is a selective, potent, first‐in‐class B‐cell lymphoma‐2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single‐dose and multiple‐dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUC∞ by 106% (90%CI, 73%–145%) and 78% (90%CI, 50%–111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC∞ by 42% (90%CI, 31%–52%) and 71% (90%CI, 66%–76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P‐glycoprotein (P‐gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P‐gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.

This publication has 27 references indexed in Scilit: