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.
References
Roberts AW, Davids MS, PageL JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.
Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17. doi:10.1158/2159-8290.CD-16-0313.
Jones AK, Freise KJ, Agarwal S, et al. Clinical predictors of venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J. 2016;18(5):1192–202. doi:10.1208/s12248-016-9927-9.
Salem AH, Agarwal S, Dunbar M, et al. Effect of low and high fat meals on the pharmacokinetics of venetoclax, a selective first-in-class Bcl-2 inhibitor. J Clin Pharmacol. 2016;56(11):1355–61. doi:10.1002/jcph.741.
Salem AH, Agarwal S, Dunbar M, et al. Pharmacokinetics of venetoclax, a novel BCL-2 inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or non-Hodgkin’s lymphoma. J Clin Pharmacol. 2016. doi:10.1002/jcph.821 (Epub ahead of print).
Agarwal S, Salem AH, Danilov AV, et al. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol. 2016. doi:10.1111/bcp.13175.
Agarwal SK, Hu B, Chien D, et al. 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;56(11):1335–43. doi:10.1002/jcph.730.
Venclexta™ (venetoclax) tablets [package insert]. North Chicago, IL and South San Francisco, CA; Abbvie Inc. and Genentech USA, Inc.; 2016.
Coumadin® Tablets (Warfarin Sodium Tablets, USP) Crystalline and Coumadin® for Injection (Warfarin for Injection USP) [package insert]. Princeton, NJ; Bristol Myers Squibb, 2011.
Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73(1):67–74.
Green KB, Silverstein RL. Hypercoagulability in cancer. Hematol Oncol Clin North Am. 1996;10:499–530.
Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71(3):115–21.
Wadelius M, Sörlin K, Wallerman O, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J. 2004;4(1):40–8.
Gschwind L, Rollason V, Daali Y, et al. Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model. Basic Clin Pharmacol Toxicol. 2013;113(4):259–65.
Frymoyer A, Shugarts S, Browne M, et al. Effect of single-dose rifampin on the pharmacokinetics of warfarin in healthy volunteers. Clin Pharmacol Ther. 2010;88(4):540–7.
Freise KJ, Jones AK, Eckert D, et al. Impact of venetoclax exposure on clinical efficacy and safety in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Pharmacokinet. 2016. doi:10.1007/s40262-016-0453-9 (Epub ahead of print).
Acknowledgements
Medical writing support was provided by Amy Rohrlack, BS, an employee of AbbVie.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Rights and permissions
About this article
Cite this article
Salem, A.H., Hu, B., Freise, K.J. et al. Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers. Clin Drug Investig 37, 303–309 (2017). https://doi.org/10.1007/s40261-016-0485-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40261-016-0485-9