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

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 bioavailabilit...

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Bibliographic Details
Published in:	Drug metabolism and disposition Vol. 44; no. 9; pp. 1450 - 1458
Main Authors:	Zajic, Stefan, Rossenu, Stefaan, Hreniuk, David, Kesisoglou, Filippos, McCrea, Jacqueline, Liu, Fang, Sun, Li, Witter, Rose, Gauthier, Don, Helmy, Roy, Joss, Darrick, Ni, Tong, Stoltz, Randall, Stone, Julie, Stoch, S Aubrey
Format:	Journal Article
Language:	English
Published:	United States 01-09-2016
Subjects:	Administration, Oral Aged Area Under Curve Biological Availability Biphenyl Compounds - administration & dosage Biphenyl Compounds - blood Biphenyl Compounds - pharmacokinetics Cross-Over Studies Female Food-Drug Interactions Half-Life Humans Infusions, Intravenous Middle Aged Postmenopause
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-News-1 ObjectType-Feature-3 content type line 23
ISSN:	1521-009X 1521-009X
DOI:	10.1124/dmd.116.069906