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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

2011; Wiley; Volume: 52; Issue: 3 Linguagem: Inglês

10.1177/0091270011399080

1552-4604

Shinichi Nagase, Michiyo Ohyama, Yoshitaka Hashimoto, Maria Small, Tomohiro Kuwayama, Steve Deacon,

Bone health and treatments

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).