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Pharmacodynamic Effects on Biochemical Markers of Bone Turnover and Pharmacokinetics of the Cathepsin K Inhibitor, ONO‐5334, in an Ascending Multiple‐Dose, Phase 1 Study
Author(s) -
Nagase Shinichi,
Ohyama Michiyo,
Hashimoto Yoshitaka,
Small Maria,
Kuwayama Tomohiro,
Deacon Steve
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011399080
Subject(s) - n terminal telopeptide , bone remodeling , bone resorption , medicine , endocrinology , pharmacodynamics , cathepsin k , pharmacokinetics , tartrate resistant acid phosphatase , osteocalcin , resorption , chemistry , osteoclast , alkaline phosphatase , biochemistry , receptor , enzyme
Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO‐5334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15‐ and 28‐day multiple‐dosing cohorts. Plasma ONO‐5334 concentration reached steady state within 2 days. Twenty‐four hours after the last dose in the 15‐day multiple‐dose cohort, 100, 300, and 600 mg once daily reduced urinary C‐terminal telopeptide of type I collagen by a mean (± standard deviation) 44.9% ± 13.6%, 84.5% ± 4.4%, and 92.5% ± 1.3%, respectively. The 28‐day cohort showed similar effects. There were far smaller effects on bone‐specific alkaline phosphatase (B‐ALP), tartrate‐resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO‐5334 was well tolerated up to 600 mg/d and for up to 28 days of multiple dosing. Multiple dosing with ONO‐5334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B‐ALP, OC) or osteoclast number (TRAP5b).