Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women

Abstract

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.

Effect of ONO-5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2-Year Results From the OCEAN Study

“…Dose‐response relationships with BMD effects have also been suggested for odanacatib, and when this is considered in conjunction with the consistently greater increases in BMD associated with ONO‐5334 50 mg bid over 100 mg qd, it seems reasonable to propose that higher trough levels or sustained inhibition rather than higher maximum plasma concentrations are more important for a more potent increase in BMD. It seems reasonable to speculate, therefore, that additional clinical benefits could be derived through manipulation of the plasma profile of ONO‐5334, perhaps via a sustained release formulation …”

Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO‐5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females

“…Among several serum markers including bone formation markers, CTX and NTX have been used in the modeling since effect on bone resorption markers was considered primary PD effect of ONO‐5334. Studies also had more sampling for these markers compared to other bone resorption markers …”

“…Serum markers of bone resorption were suppressed promptly (at least within 4 hours), and the maximum suppression was observed mostly within 8 hours after dosing of ONO‐5334 IRT. Compared with the IRT, the SRT shows reduced maximum concentration (C max ), greater plasma concentration at 24 hours after dosing (C 24h ) but comparable area under the concentration‐time curve (AUC) with clear dose‐dependent suppression on bone resorption markers and greater suppressive effect versus the IRT dose for dose . These phenomena were observed in both Caucasian and Japanese.…”

Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish

“…1). 22,23 Odanacatib and balicatib are reversible covalent Cat K inhibitors carrying a cyano group that can form a covalent bond with C25 of the active pocket in Cat K.…”