{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:43:12Z","timestamp":1785188592917,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T00:00:00Z","timestamp":1587081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009947","name":"Merck Sharp & Dohme Corp.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Merck & Co., Inc., Kenilworth, NJ, USA"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase\u00a02\/3 studies. Data from multiple phase\u00a01 (P005, P025, and P014), phase\u00a02b (P004 and P022), and phase\u00a03 (Long\u2010Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase\u00a01, 514 from phase\u00a02b, and 664 from phase\u00a03) who received weekly oral odanacatib doses ranging from 3 to 100\u00a0mg. A 1\u2010compartment model with first\u2010order absorption, dose\u2010dependent relative bioavailability (F1), and first\u2010order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3\u2010mg oral dose to 24.5% for a 100\u2010mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high\u2010fat breakfast, and a study effect on F1. All fixed\u2010 and random\u2010effects parameters were estimated with good precision (%standard error of the mean \u226429.5%). This population PK analysis provides insights into intrinsic\u2010 and extrinsic\u2010factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic\u2010factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80\u20101.21) even in subjects aged &gt;80 years, or in subsets with multiple combinations of factors.<\/jats:p>","DOI":"10.1002\/jcph.1606","type":"journal-article","created":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T18:35:41Z","timestamp":1587148541000},"page":"1107-1123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women"],"prefix":"10.1002","volume":"60","author":[{"given":"David","family":"Jaworowicz","sequence":"first","affiliation":[{"name":"Cognigen Corporation (a SimulationsPlus Company)  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Bihorel","sequence":"additional","affiliation":[{"name":"Cognigen Corporation (a SimulationsPlus Company)  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Zajic","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  Kenilworth New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Aubrey","family":"Stoch","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  Kenilworth New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Humphrey","sequence":"additional","affiliation":[{"name":"Cognigen Corporation (a SimulationsPlus Company)  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline B.","family":"McCrea","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  Kenilworth New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Stone","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc.  Kenilworth New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-011-0085-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.12.047"},{"issue":"10","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nrd.2016.207","article-title":"Merck & Co. drops osteoporosis drug odanacatib","volume":"15","author":"Mullard A","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13869"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04471.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.069906"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.60"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.056580"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2011.12.004"},{"key":"e_1_2_9_11_1","unstructured":"United States Food and Drug Administration.Collection of race and ethnicity data in clinical trials\u2014Guidance for Industry and Food and Drug Administration Staff.https:\/\/www.fda.gov\/downloads\/regulatoryinformation\/guidances\/ucm126396.pdf. 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