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

• Published in: Clinical drug investigation Vol. 37; no. 3; pp. 303 - 309
• Main Authors: Salem, Ahmed Hamed, Hu, Beibei, Freise, Kevin J., Agarwal, Suresh K., Sidhu, Dilraj S., Wong, Shekman L.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2017; Springer Nature B.V
• Subjects: Adult; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Area Under Curve; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cross-Over Studies; Cytochrome; Drug dosages; Drug Interactions; Female; Glycoproteins; Half-Life; Humans; Internal Medicine; International Normalized Ratio; Leukemia; Lymphoma; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Phlebotomy; Proteins; Rodents; Short Communication; Sulfonamides - pharmacology; Warfarin - pharmacokinetics; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia Patient; Terminal Phase Elimination; Warfarin; Maximum Observe Plasma Concentration
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-016-0485-9

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.