Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans

作者：Kassahun Kelem^*; McIntosh Ian; Koeplinger Kenneth; Sun Li; Talaty Jennifer E; Miller Deborah L; Dixon Russell; Zajic Stefan; Stoch S Aubrey

来源：Drug Metabolism and Disposition, 2014, 42(5): 818-827.

DOI：10.1124/dmd.113.056580

Odanacatib is a selective inhibitor of the cathepsin K enzyme that is expressed in osteoclasts involved in the degradation of bone organic matrix, and is being developed as a novel treatment of osteoporosis. Odanacatib has demonstrated increases in bone mineral density in postmenopausal women and is undergoing a pivotal phase III trial. The absorption, metabolism, and excretion of [C-14]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 mu Ci). Plasma, urine, and fecal samples were collected at intervals up to 34 days postdose. The pharmacokinetics of odanacatib were characterized by slow absorption (mean time to achieve maximum plasma concentration of 14.2 hours) and long apparent elimination half-life (mean t(1/2) 96.7 hours); 74.5% of the dose was recovered in feces and 16.9% in urine, resulting in a total recovery of 91.4%. Seven metabolites were identified in urine; the major pathway (methyl hydroxylation producing M8 and its derivatives) was largely dependent on CYP3A. Metabolites and odanacatib accounted for 77% and 23% of urinary radioactivity, respectively. In fecal extracts, the only radioactive components identified were odanacatib (60.9%) and M8 (9.5%). The fraction of odanacatib in feces derived from absorbed drug was estimated using a bioavailability value obtained from the results of a separate intravenous study. Collectively, the data indicate that odanacatib has a long t(1/2) on account of its low metabolic intrinsic clearance, and that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for similar to 70% and similar to 30% of the clearance of odanacatib in humans.

• 出版日期2014-5