ODANACATIB DOES NOT INFLUENCE THE SINGLE DOSE PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN

Main Article Content

S Aubrey Stoch
Rose Witter
David Hreniuk
Chengcheng Liu
Stefan Zajic
Anish Mehta
Patricia Chandler
Denise Morris
Hongwei Xue
Andrew Denker
John A Wagner

Keywords

Odanacatib, warfarin, CYP2C9, CYP3A4, CYP2C19, CYP1A2

Abstract

Background
Warfarin is an anticoagulant with a narrow therapeutic index that is involved in a number of drug-drug interactions.



Objectives
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.

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