Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans
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...
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Published in | Drug metabolism and disposition Vol. 42; no. 5; pp. 818 - 827 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.05.2014
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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 µCi). 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 t1/2 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 t1/2 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. |
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AbstractList | 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 µCi). 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 t1/2 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 t1/2 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. 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 [ super(14)C]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 sub(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 sub(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. |
Author | McIntosh, Ian Dixon, Russell Talaty, Jennifer E Stoch, S Aubrey Sun, Li Miller, Deborah L Zajic, Stefan Kassahun, Kelem Koeplinger, Kenneth |
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Cites_doi | 10.1359/jbmr.091035 10.1111/j.1365-2125.2012.04471.x 10.1038/clpt.2009.60 10.1007/s11657-013-0136-1 10.1210/jc.2012-2972 10.1002/jbmr.1475 10.1210/jc.2011-2332 10.1124/dmd.110.037184 10.1016/j.rcl.2010.02.010 10.1016/S0140-6736(10)62349-5 10.5414/CP201864 10.1002/jbmr.212 10.1016/j.bmcl.2007.12.047 10.1016/j.jchromb.2011.12.004 10.1002/jbmr.1477 10.1007/s002160051521 10.1038/sj.clpt.6100450 |
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References | 2019081311215178000_42.5.818.16 2019081311215178000_42.5.818.15 2019081311215178000_42.5.818.14 Bone (2019081311215178000_42.5.818.2) 2010; 25 Sun (2019081311215178000_42.5.818.20) 2012; 885-886 2019081311215178000_42.5.818.19 2019081311215178000_42.5.818.18 2019081311215178000_42.5.818.9 2019081311215178000_42.5.818.8 Krimmer (2019081311215178000_42.5.818.12) 1987; 111 2019081311215178000_42.5.818.13 2019081311215178000_42.5.818.7 2019081311215178000_42.5.818.6 2019081311215178000_42.5.818.11 2019081311215178000_42.5.818.5 2019081311215178000_42.5.818.4 2019081311215178000_42.5.818.3 2019081311215178000_42.5.818.1 Iki (2019081311215178000_42.5.818.10) 2012; 22 Stoch (2019081311215178000_42.5.818.17) 2013; 20 |
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SubjectTerms | Adolescent Adult Animals ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biotransformation Biphenyl Compounds - blood Biphenyl Compounds - pharmacokinetics Biphenyl Compounds - urine Bone Density Conservation Agents - blood Bone Density Conservation Agents - pharmacokinetics Bone Density Conservation Agents - urine Cathepsin K - antagonists & inhibitors Cells, Cultured Cytochrome P-450 Enzyme System - metabolism Feces - chemistry Hepatocytes - drug effects Hepatocytes - metabolism Humans Male Microsomes, Liver - drug effects Microsomes, Liver - enzymology Microsomes, Liver - metabolism Middle Aged Rats Substrate Specificity Tissue Distribution Young Adult |
Title | Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans |
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