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

Suresh K. Agarwal, Beibei Hu, David Chien, Shekman L. Wong, Ahmed Hamed Salem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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 Cmaxand AUCby 106% (90%CI, 73%–145%) and 78% (90%CI, 50%–111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmaxand AUCby 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 Cmaxand 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.

Original languageEnglish
Pages (from-to)1335-1343
Number of pages9
JournalJournal of Clinical Pharmacology
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • ABT-199/GDC-0199
  • BCL-2
  • CYP3A4
  • OATP
  • P-glycoprotein
  • interaction
  • pharmacokinetics
  • rifampin
  • venetoclax

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this