title: Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women.
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.
authors.affiliation: 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.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Isaias Noel
authors.initials: IN
authors.lastname: Gendrano
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Jeffers
authors.forename: Chantal
authors.initials: C
authors.lastname: Mahon
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.forename: Kate
authors.initials: K
authors.lastname: Mostoller
authors.forename: Stefan
authors.initials: S
authors.lastname: Zajic
authors.forename: Denise
authors.initials: D
authors.lastname: Morris
authors.forename: Jessie
authors.initials: J
authors.lastname: Lee
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D000368:Aged; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017698:Postmenopause; D012737:Sex Factors
chemical_list: D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; D056657:Cathepsin K; C527128:odanacatib