Abstract
A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable 13C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low–extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.
Footnotes
- Received February 22, 2016.
- Accepted July 8, 2016.
This study, including editorial assistance, was funded by Merck & Co., Inc., Kenilworth, NJ. S.Z., S.R., D.H., F.K., J.M., F.L., L.S., R.W., D.G., R.H., D.J., T.N., J.S., S.A.S. are employees or former employees of Merck Sharp & Dohme Corp. and may own stock and/or hold stock options in the company. R.S. has no competing interests, as defined by the American Society for Clinical Pharmacology and Therapeutics, or other interests that might be perceived to influence the results and/or discussion reported in this article.
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- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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