Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers
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Background and Objective
Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics.
Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout. On day 1 of period 2, subjects concomitantly received a single 400 mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9 days.
Modest increases of 18 to 28% were observed in the maximum observed plasma concentration (C max) and area under the curve from time zero to infinity (AUC∞) of both R- and S-warfarin.
Due to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.
KeywordsWarfarin Chronic Lymphocytic Leukemia Chronic Lymphocytic Leukemia Patient Terminal Phase Elimination Maximum Observe Plasma Concentration
Medical writing support was provided by Amy Rohrlack, BS, an employee of AbbVie.
Compliance with Ethical Standards
AbbVie and Genentech/Roche provided financial support for the studies and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review and approval of the manuscript. Venetoclax is being developed in a collaboration between AbbVie and Genentech/Roche.
Conflict of interest
Ahmed Hamed Salem, Beibei Hu, Kevin J. Friese, Suresh K. Agarwal, Dilraj S. Sidhu, and Shekman L. Wong are employees of AbbVie and may hold AbbVie stock or stock options.
The study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki and its amendments, International Conference for Harmonisation–Good Clinical Practice guidelines, and local guidelines and regulations. The protocol and informed consent forms were approved by the institutional review board/ethics committee.
Written informed consent was obtained from all subjects before being included in the study.
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