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Clinical Drug Investigation

, Volume 37, Issue 3, pp 303–309 | Cite as

Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers

  • Ahmed Hamed SalemEmail author
  • Beibei Hu
  • Kevin J. Freise
  • Suresh K. Agarwal
  • Dilraj S. Sidhu
  • Shekman L. Wong
Short Communication

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Warfarin Chronic Lymphocytic Leukemia Chronic Lymphocytic Leukemia Patient Terminal Phase Elimination Maximum Observe Plasma Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Medical writing support was provided by Amy Rohrlack, BS, an employee of AbbVie.

Compliance with Ethical Standards

Funding

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.

Ethical approval

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.

Informed consent

Written informed consent was obtained from all subjects before being included in the study.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Clinical Pharmacology and PharmacometricsAbbVie Inc.North ChicagoUSA
  2. 2.Department of Clinical Pharmacy, Faculty of PharmacyAin Shams UniversityCairoEgypt

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