The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women.

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 (13)C-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.