title: Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.
abstract: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration.
  
  
  BACKGROUND
  Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration.
  
  
  METHODS
  This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study.
  
  
  RESULTS
  Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern.
  
  
  CONCLUSIONS
  Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.
authors.affiliation: Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK. r.eastell@sheffield.ac.uk.|Metabolic Bone Centre, Northern General Hospital, Herries Road, Sheffield, South Yorkshire, S5 7AU, UK. r.eastell@sheffield.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Eastell
authors.affiliation: Surrey Clinical Research Centre, University of Surrey, Guildford, UK.
authors.forename: D-J
authors.initials: DJ
authors.lastname: Dijk
authors.affiliation: Ono Pharma UK Ltd, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Small
authors.affiliation: Surrey Clinical Research Centre, University of Surrey, Guildford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Greenwood
authors.affiliation: Ono Pharma UK Ltd, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Sharpe
authors.affiliation: Ono Pharma UK Ltd, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yuba
authors.affiliation: Ono Pharmaceutical Co., Ltd, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: Ono Pharma UK Ltd, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Deacon
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D001862:Bone Resorption / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D057906:Circadian Clocks / Q000502:physiology; D024042:Collagen Type I / Q000097:blood; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control; D010455:Peptides / Q000097:blood; D017698:Postmenopause / Q000097:blood / Q000502:physiology; D016037:Single-Blind Method; D053778:Thiazolidines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; C560865:ONO-5334; D010455:Peptides; D053778:Thiazolidines; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K
keywords: Anti-resorptive; Bone resorption; Menopause; Osteoporosis