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 |
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| Affiliation: | 1. Research Promotion, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan;2. Translational Medicine Center, Ono Pharmaceutical Co., Ltd., Shimamoto, Osaka, Japan;1. Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA;2. Department of Mechanical Engineering, University of Delaware, Newark, DE 19716, USA;3. Department of Mechanical and Industrial Engineering, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada;1. Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA;2. Drexel University, Philadelphia, PA, USA;3. Department of Medicine, Rutgers-Robert Wood Johnson University Hospital, USA;1. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK;2. MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK;3. Victoria University, Wellington, New Zealand;4. NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford OX3 5UG, UK;5. NIHR Nutrition Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Trust, Southampton General Hospital, Southampton SO16 6YD, UK;1. Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Bron, France;2. INSERM, UMR 1033, Lyon, France;3. Université de Lyon, Lyon France;4. Service de Chirurgie Orthopédique Pédiatrique, Hôpital Femme Mère Enfant, Bron, France;5. Service de Néphrologie, CHU, Rouen, France |
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| 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 100 mg 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. |
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