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.
RCT Entities:
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.
Authors: Julie A Stone; Jacqueline B McCrea; Rose Witter; Stefan Zajic; S Aubrey Stoch Journal: Br J Clin Pharmacol Date: 2019-03-18 Impact factor: 4.335