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.
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Agarwal SK, Hu B, Chien D, Wong SL, Salem AH
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.
J Clin Pharmacol. 2016 Mar 7. doi: 10.1002/jcph.730.
- PubMed ID
- 26953185 [ View in PubMed]
- Abstract
Venetoclax is a selective, potent, first-in-class Bcl-2 inhibitor that 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 Period 1 Day 1, Period 2 Days 1 and 14. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUCinfinity by 106% (90% CI: 73%-145%) and 78% (90% CI: 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUCinfinity by 42% (90% CI: 52%-31%) and 71% (90% CI: 76%-66%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-gp inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose rifampin which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results indicate that venetoclax is a P-gp substrate and CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax. This article is protected by copyright. All rights reserved.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Venetoclax Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Venetoclax P-glycoprotein 1 Protein Humans NoSubstrateInhibitorDetails - Drug Reactions
Reaction Details
