Document Detail

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.
MedLine Citation:
PMID:  23013236     Owner:  NLM     Status:  MEDLINE    
AIMS: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.
METHODS: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women).
RESULTS: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction.
CONCLUSIONS: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.
S Aubrey Stoch; Stefan Zajic; Julie A Stone; Deborah L Miller; Lucas van Bortel; Kenneth C Lasseter; Barnali Pramanik; Caroline Cilissen; Qi Liu; Lida Liu; Boyd B Scott; Deborah Panebianco; Yu Ding; Keith Gottesdiener; John A Wagner
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  75     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-08     Completed Date:  2013-10-01     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1240-54     Citation Subset:  IM    
Copyright Information:
© 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Administration, Oral
Aged, 80 and over
Area Under Curve
Biphenyl Compounds / adverse effects,  pharmacokinetics,  pharmacology*
Bone Resorption / metabolism
Cathepsin K / antagonists & inhibitors*
Dose-Response Relationship, Drug
Double-Blind Method
Drug Administration Schedule
Enzyme Inhibitors / adverse effects,  pharmacokinetics,  pharmacology*
Middle Aged
Osteoporosis / drug therapy*,  metabolism
Young Adult
Reg. No./Substance:
0/Biphenyl Compounds; 0/Enzyme Inhibitors; EC K; N673F6W2VH/odanacatib

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