{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:28:50Z","timestamp":1790267330654,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:p>Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in\u2010patient studies. Following 3\u00a0weeks of 50\u00a0mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1\u00a0\u03bcM\u00a0h, the concentration at 168 hours was 126\u00a0nM and the harmonic mean apparent terminal half\u2010life was 84.8\u00a0hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13\u00a0mL\/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C\u2010telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline\/Cr (approximately 30%), with an increase in serum cross\u2010linked carboxy\u2010terminal telopeptide of type 1 collagen (approximately 55%). The 50\u2010mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO\u20105334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation\u2010sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build\u2010up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.<\/jats:p>","DOI":"10.1111\/bcp.13869","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T02:54:33Z","timestamp":1548039273000},"page":"1072-1083","source":"Crossref","is-referenced-by-count":58,"title":["Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis"],"prefix":"10.1111","volume":"85","author":[{"given":"Julie A.","family":"Stone","sequence":"first","affiliation":[{"name":"Merck &amp; Co., Inc. 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