Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women.
A sustained-release tablet (SRT) of ONO-5334 was compared to the immediate-release tablet (IRT) dose, which demonstrated effects on bone mineral density (BMD) comparable to those of therapy with alendronate. The single-dose phase was a randomized, partial single-blind, crossover study where 50-, 100-, and 300-mg SRTs and 300-mg IRTs were administered to nine post-menopausal women. The multiple-dose phase was a randomized, double-blind, placebo-controlled, parallel-group study where 100- and 300-mg SRTs, or placebo were administered to 24 women. After a single administration of a 300-mg SRT, mean C max was 3.3-fold lower, mean AUCinf was 0.83-fold lower and mean C 24h was 5.4-fold higher compared to the 300-mg IRT. Repeated SRT dosing did not significantly affect PK, although C 24h increased slightly. After a single ONO-5334 dose, serum CTX-I was suppressed by ~50 % within 1 h, reaching maximum suppression 6 h post-dose. Greater suppression was maintained longer by the 300-mg SRT vs. the 300-mg IRT. Second morning void and cumulative urine CTX-I showed clear dose-response effects at/over 24 h for SRT, with maximum suppression occurring at/over 24 h (except 50- and 300-mg cumulative urine). Repeated dosing suggested greater suppression of urine CTX-I. Compared with the IRT, the SRT showed reduced C max, greater C 24h, and slightly reduced AUCinf dose for dose. The SRT showed clear dose-response suppression on bone resorption and greater efficacy dose for dose vs. the IRT.
Drug Development, ONO PHARMA UK LTD, MidCity Place, 71 High Holborn, London, WC1V 6EA, UK, s.nagase@ono.co.jp.
Shinichi
S
Nagase
Michiyo
M
Ohyama
Yoshitaka
Y
Hashimoto
Maria
M
Small
John
J
Sharpe
Junichiro
J
Manako
Tomohiro
T
Kuwayama
Steve
S
Deacon
D000368:Aged; D019386:Alendronate / Q000737:chemistry; D019540:Area Under Curve; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000652:urine; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy*; D017698:Postmenopause; D016037:Single-Blind Method; D053778:Thiazolidines / Q000737:chemistry* / Q000493:pharmacokinetics
D024042:Collagen Type I; D003692:Delayed-Action Preparations; C560865:ONO-5334; D053778:Thiazolidines; D056657:Cathepsin K; D019386:Alendronate