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J Clin Endocrinol Metab. 2014 Feb;99(2):552-60. doi: 10.1210/jc.2013-1688. Epub 2013 Nov 25.

Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women.

Author information

1
Merck & Co, Inc (M.S.A., I.N.G., C.L., C.M., A.M., K.M., S.Z., S.A.S.), Whitehouse Station, New Jersey 08889; and Covance Clinical Research Unit, Inc (S.J., D.M., J.L.), Austin, Texas 78752.

Abstract

BACKGROUND:

Odanacatib is a cathepsin K inhibitor in development for the treatment of osteoporosis. Evaluation of therapies to ensure that treatment effects are relevant regardless of sex is clinically important.

METHODS:

In this double-blind, randomized controlled trial, older men (aged 50-75 years) and postmenopausal women (aged 45-75 years) were given odanacatib 50 mg once weekly or placebo for 4 weeks. Pharmacodynamic (PD) evaluation measured weighted average inhibition (WAI) of urine amino-terminal cross-linked telopeptide of type I collagen/creatinine (uNTx/Cr) after odanacatib administration. Pharmacokinetic (PK) parameter data were collected, and an analysis of sex as a factor in the PK/PD relationship was conducted. Adverse events were monitored. The hypotheses were that WAI of uNTx/Cr would be >40% (including >40% for the lower limit of the 90% confidence intervals [CIs]) for older men and postmenopausal women, that there would be no important differences in area under the curve from 0 to 168 hours (AUC0-168 h) between men and women, and that odanacatib would be safe and well tolerated.

RESULTS:

A total of 44 subjects (32 men and 12 women) were randomized. The least squares mean WAI (uNTx/Cr) at week 4 was 42.8% (90% CI, 35.5%-49.3%) for men and 42.7% (90% CI, 30.3%-52.9%) for women; mean values were >40%, but lower bounds were <40% as prespecified in the primary hypothesis. The differences among men and women in PD parameters were not meaningful (0.1; 90% CI, -14.7 to 14.9). PK parameters for both groups were comparable (geometric mean ratio of AUC0-168 h, 0.90; 90% CI, 0.75-1.07). A PK/PD analysis found that the EC50 and maximum fractional inhibition were similar in male and female subjects. There were no notable or serious adverse events in this study.

CONCLUSIONS:

Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01068262.

PMID:
24276460
DOI:
10.1210/jc.2013-1688
[Indexed for MEDLINE]

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