ODANACATIB DOES NOT INFLUENCE THE SINGLE DOSE PHARMACOKINETICS AND PHARMACODYNAMICS OF WARFARIN
Main Article Content
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.
References
2. Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 2011;26:242-51.
3. Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: 5 years of continued therapy in a phase 2 study. J Bone Miner Res 2012 Nov;27(11):2251-8. J Bone Miner Res. doi: 10.1002/jbmr.1695. [Epub ahead of print]
4. Hirsh J. Oral anticoagulant drugs N Engl J Med 1991;324:1865-75.
5. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
6. Product Label. COUMADIN® TABLETS (Warfarin Sodium Tablets, USP) Crystalline COUMADIN® FOR INJECTION (Warfarin Sodium for Injection, USP). http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf (accessed September 2012)
7. Johnston M, Harrison L, Moffat K, Willan A, Hirsh J. Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio. J Lab Clin Med 1996;128:214-17.
8. Serlin MJ, Breckenridge AM. Drug interactions with warfarin. Drugs 1983;25:610-20.
9. Herman D, Locatelli I, Grabnar I, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics 2005;J5:193-202.
10. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67-74.
11. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992;5:54-9.
12. Stoch SA, Zajic S, Stone JA, et al. Odanacatib, a selective Cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics - results from single oral dose studies in healthy volunteers. Br J Clin Pharmacol 2012. doi: 10.1111/j.1365-2125.2012.04471.x. [Epub ahead of print].
13. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2008;133:257S–8S [8th edition].
14. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008;71:1084-9.
15. Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P, CHANT Investigators. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008;39:2993-96.