title: Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers.
abstract: 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 (Cmax) 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.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA. ahmed.salem@abbvie.com.|Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. ahmed.salem@abbvie.com.
authors.forename: Ahmed Hamed
authors.identifier: http://orcid.org/0000-0002-9261-1583
authors.initials: AH
authors.lastname: Salem
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Hu
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Freise
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Dilraj S
authors.initials: DS
authors.lastname: Sidhu
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008875:Middle Aged; D013449:Sulfonamides / Q000494:pharmacology*; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D014859:Warfarin; C579720:venetoclax