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Research ArticleArticle

Disposition and Metabolism of the Cathepsin K Inhibitor Odanacatib in Humans

Kelem Kassahun, Ian McIntosh, Kenneth Koeplinger, Li Sun, Jennifer E. Talaty, Deborah L. Miller, Russell Dixon, Stefan Zajic and S. Aubrey Stoch
Drug Metabolism and Disposition May 2014, 42 (5) 818-827; DOI: https://doi.org/10.1124/dmd.113.056580
Kelem Kassahun
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Ian McIntosh
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Kenneth Koeplinger
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Li Sun
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Jennifer E. Talaty
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Deborah L. Miller
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Russell Dixon
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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Stefan Zajic
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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S. Aubrey Stoch
Merck Research Laboratories, West Point, Pennsylvania (K.Ka., I.M., K.Ko., L.S., J.E.T., S.Z.); Merck Research Laboratories, Rahway, New Jersey (D.L.M., S.A.S.); and Covance Clinical Research, Madison, Wisconsin (R.D.)
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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 [14C]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.

Footnotes

    • Received December 23, 2013.
    • Accepted February 18, 2014.
  • This study was sponsored by Merck & Co., Inc., Whitehouse Station, NJ. Editorial assistance was provided by Gary Dever, Ph.D., of Complete Medical Communications, Parsippany, NJ. This assistance was funded by Merck & Co., Inc., Whitehouse Station, NJ.

  • dx.doi.org/10.1124/dmd.113.056580.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (5)
Drug Metabolism and Disposition
Vol. 42, Issue 5
1 May 2014
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Research ArticleArticle

Absorption, Metabolism, and Excretion of Odanacatib

Kelem Kassahun, Ian McIntosh, Kenneth Koeplinger, Li Sun, Jennifer E. Talaty, Deborah L. Miller, Russell Dixon, Stefan Zajic and S. Aubrey Stoch
Drug Metabolism and Disposition May 1, 2014, 42 (5) 818-827; DOI: https://doi.org/10.1124/dmd.113.056580

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Research ArticleArticle

Absorption, Metabolism, and Excretion of Odanacatib

Kelem Kassahun, Ian McIntosh, Kenneth Koeplinger, Li Sun, Jennifer E. Talaty, Deborah L. Miller, Russell Dixon, Stefan Zajic and S. Aubrey Stoch
Drug Metabolism and Disposition May 1, 2014, 42 (5) 818-827; DOI: https://doi.org/10.1124/dmd.113.056580
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