title: An oral cathepsin K inhibitor ONO-5334 inhibits N-terminal and C-terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women.
abstract: Relationships between the plasma concentration of a cathepsin K inhibitor (ONO-5334) and inhibition of bone resorption markers N-telopeptide of type I collagen (NTX) and C-telopeptide of type I collagen (CTX) in serum and urinary NTX/creatinine and CTX/creatinine were examined in 10 postmenopausal women. The subjects received slow-release tablets of 100mg ONO-5534 under fasted or fed conditions in a study with a crossover design. Inhibition of serum NTX and CTX levels and plasma concentrations of ONO-5334 were monitored at 0, 24, 48 and 168 h after dosing. Changes in urinary NTX/creatinine and CTX/creatinine levels in second morning urine were evaluated on 0, 1, 2 and 7 days after dosing. Data were analyzed using sigmoid maximal drug effect (Emax) models. The maximal inhibition, estimated Emax values, were -31.8% for serum NTX, -53.1% for serum CTX, -67.2% for urinary NTX/creatinine, and -95.2% for urinary CTX/creatinine. The estimated half maximal effective plasma concentrations (EC50) of ONO-5334 and confidence intervals were 1.79 (1.01 to 3.16) ng/mL for serum NTX, 2.07 (1.63 to 2.62) ng/mL for serum CTX, 1.85 (1.30 to 2.61) ng/mL for urinary NTX/creatinine, and 1.98 (0.94 to 3.76) ng/mL for urinary CTX/creatinine. EC50 values for the four crosslinks did not significantly differ, as indicated by the overlapping 95% confidence intervals. The highest signal-to-noise ratio was achieved with serum CTX, and was 2-fold higher than that on serum NTX. Inhibition for serum NTX and CTX, and urinary NTX/creatinine and CTX/creatinine by ONO-5334 were all correlated with correlation coefficients ranging from 0.55 to 0.80. In conclusion, data of ONO-5334 slow-releasing tablets in postmenopausal women were well fitted in Emax model. In all measured telopeptides, the maximal inhibition was obtained at urinary CTX/creatinine level, but serum CTX had the highest signal-to-noise ratio. Inhibition for all measured telopeptides by ONO-5334 were all correlated. The estimated half maximal effective plasma concentrations were not significantly different between all measured telopeptides.
authors.affiliation: Research Promotion, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan. Electronic address: mak.tanaka@ono.co.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Translational Medicine Center, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Translational Medicine Center, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hasegawa
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000652:urine; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000037:antagonists & inhibitors / Q000097:blood* / Q000652:urine*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood* / Q000187:drug effects / Q000652:urine*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D003692:Delayed-Action Preparations; C560865:ONO-5334; D053778:Thiazolidines; D003094:Collagen; D056657:Cathepsin K
keywords: CTX; Cathepsin K, ONO-5334; E(max) model; NTX; Pharmacokinetics