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 Cmax was 3.3-fold lower, mean AUCinf was 0.83-fold lower and mean C24h was 5.4-fold higher compared to the 300-mg IRT. Repeated SRT dosing did not significantly affect PK, although C24h 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 Cmax, greater C24h, 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.
Cathepsin K inhibitor Osteoporosis Sustained-release formulation CTX-I ONO-5334