title: Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO-5334 after ascending single doses in post menopausal women.
abstract: OBJECTIVE
  To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334.
  
  
  METHODS
  A double-blind, placebo-controlled, randomized study was carried out in 52 healthy post menopausal females. Single ascending doses of ONO-5334 (3-600 mg) were evaluated in six cohorts. The effect of food was studied at ONO-5334 100 mg.
  
  
  RESULTS
  Across the doses tested, mean ONO-5334 C(max) occurred 0.5-1.0 h after dosing and the the t(1/2) ranged from 9.1 to 22 h. Linear increases in C(max) and AUC(0,∞) were observed in the 3-300 mg and 3-600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) C(max) and AUC(0,∞) for ONO-5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)-fold greater than fasted, respectively. ONO-5334 significantly reduced serum bone resorption markers within 4 h vs. placebo. Statistical significance was achieved for ONO-5334 doses ≥30 mg for C-terminal telopeptide of type 1 collagen (CTX) and ≥300 mg for N-terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO-5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of -32%, -59%, -60% and -66% for 30, 100, 300 and 600 mg ONO-5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs. placebo. ONO-5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship.
  
  
  CONCLUSIONS
  ONO-5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3-300 mg, with clear suppression of urinary bone resorption markers at doses ≥100 mg for serum markers at 24 h. ONO-5334 was well tolerated up to 600 mg day(-1) when administered to healthy post menopausal women.
authors.affiliation: Clinical Development, ONO PHARMA UK LTD, London, United Kingdom. s.nagase@ono.co.jp
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nagase
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Maria
authors.initials: M
authors.lastname: Small
authors.forename: Michiyo
authors.initials: M
authors.lastname: Ohyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kuwayama
authors.forename: Steve
authors.initials: S
authors.lastname: Deacon
mesh_terms: D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism*; D010455:Peptides / Q000097:blood / Q000652:urine; D017698:Postmenopause; D053778:Thiazolidines / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; C560865:ONO-5334; D010455:Peptides; D053778:Thiazolidines; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K