Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans

Abstract

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 [ 14 C]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 mCi). 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 ∼70% and ∼30% of the clearance of odanacatib in humans.

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

“…Based on the amounts of odanacatib recovered in feces and urine in the human absorption, distribution, metabolism, and excretion study, it can be estimated that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for approximately 70% and 30%, respectively, of the clearance of odanacatib in humans (calculations supporting this estimate are described in detail by Kassahun et al, 2014; absorbed drug in feces accounts for approximately 20% of the dose).…”

“…PK in humans are characterized by a relatively long apparent terminal half-life (t 1/2 ) of approximately 80 hours, which is consistent with low metabolic intrinsic clearance, and less than dose-proportional increases in concentration and exposure [area under the curve (AUC)] with increasing dose. Metabolism (principally mediated by CYP3A) and biliary and/or intestinal excretion of intact parent compound account for approximately 70% and 30%, respectively, of the clearance of odanacatib in humans (Kassahun et al, 2014). Odanacatib is a biopharmaceutics classification system class II compound with high permeability (consistent with absorption via passive diffusion) and very low solubility across the gastrointestinal tract (,0.001 mg/ml in water).…”

“…The pharmacokinetics (PK) of odanacatib have been investigated in phase 1 single-dose (Stoch et al, 2013) and multiple-dose (Stoch et al, 2009;Anderson et al, 2014) studies. In addition, an absorption, distribution, metabolism, and excretion study was conducted in humans (Kassahun et al, 2014), after detailed characterization of metabolism in rats, dogs, and monkeys (Kassahun et al, 2011). PK in humans are characterized by a relatively long apparent terminal half-life (t 1/2 ) of approximately 80 hours, which is consistent with low metabolic intrinsic clearance, and less than dose-proportional increases in concentration and exposure [area under the curve (AUC)] with increasing dose.…”

Odanacatib for the treatment of osteoporosis

“…It is well tolerated without gastrointestinal side effects, which can be an issue with oral bisphosphonates [26]. It has low urinary excretion and is predominantly metabolized by CYP3A and therefore its elimination is not highly dependent on renal function and creatinine clearance [56]. Similar to denosumab, odanacatib's effects on bone turnover markers are reversible [30].…”

Curcumin affords protection against valproic acid induced teratogenicity by curtailing oxidative stress and inhibiting CYP2C9 activity

“…b-Oxidation converts VPA into (E)-2-ene-VPA which acts as an anticonvulsant 14 and the formation of (E)-2-4-diene-VPA, responsible for the toxicity, [15][16][17] is catalyzed mainly by the CYP2C9 (a subfamily of cytochrome P-450) enzyme, 18 hence, it may be hypothesized to be associated with the induction of birth defects. b-Oxidation converts VPA into (E)-2-ene-VPA which acts as an anticonvulsant 14 and the formation of (E)-2-4-diene-VPA, responsible for the toxicity, [15][16][17] is catalyzed mainly by the CYP2C9 (a subfamily of cytochrome P-450) enzyme, 18 hence, it may be hypothesized to be associated with the induction of birth defects.…”