title: Odanacatib does not influence the single dose pharmacokinetics and pharmacodynamics of warfarin.
abstract: BACKGROUND
  Warfarin is an anticoagulant with a narrow therapeutic index that is involved in a number of drug-drug interactions.
  
  
  OBJECTIVE
  This study evaluates the potential effect of odanacatib (a cathepsin K inhibitor in development for the treatment of osteoporosis) on the pharmacokinetics and pharmacodynamics of warfarin.
  
  
  METHODS
  In a randomized, open-label, two-period fixed-sequence design, 13 healthy, postmenopausal female subjects received two different treatments (Treatment A: a single dose of 30 mg warfarin; Treatment B: 3 once-weekly doses of 50 mg odanacatib with 30 mg warfarin co-administered with the last dose). Warfarin R(+) and S(-) enantiomer concentrations and prothrombin time were measured at pre-dose and at specified time points over 168 hours in each treatment period. Statistical analysis was performed using linear mixed effects model.
  
  
  RESULTS
  Odanacatib was generally well tolerated when co-administered with warfarin in this study. The GMRs (95% confidence intervals [CI]) for plasma AUC0-∞ of warfarin+odanacatib/warfarin alone were 0.99 (0.94, 1.03) for warfarin R(+) and 1.00 (0.97, 1.03) for warfarin S(-), consistent with a lack of interaction between odanacatib and warfarin; results for Cmax, Tmax, and terminal t½ provided also demonstrated no interaction. The GMR (warfarin + odancacatib/warfarin alone) and 95% CI for the statistical comparison of INR AUC(0-168 hr) was 1.01 (0.98, 1.04).
  
  
  CONCLUSIONS
  The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of odanacatib, indicating that odanacatib is not a clinically important inhibitor of CYPs 2C9, 3A4, 2C19, or 1A2.
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
authors.forename: Rose
authors.initials: R
authors.lastname: Witter
authors.forename: David
authors.initials: D
authors.lastname: Hrenuik
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.forename: Stefan
authors.initials: S
authors.lastname: Zajic
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.forename: Patricia
authors.initials: P
authors.lastname: Chandler
authors.forename: Denise
authors.initials: D
authors.lastname: Morris
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xue
authors.forename: Andrew
authors.initials: A
authors.lastname: Denker
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000097:blood; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D001713:Biphenyl Compounds; D014859:Warfarin; D056657:Cathepsin K; C527128:odanacatib