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

Abstract

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

Modeling and simulation of bone mineral density response from a phase 2 study of ONO‐5334, a new cathepsin K inhibitor, to support dose selection in osteoporosis

“…A population PK model simultaneously analyzing both ONO‐5334 IRT and SRT data was developed using intensive PK sampling collected in 4 phase 1 studies (protocol numbers: ONO‐5334POE001, ONO‐5334‐01, ONO‐5334POE006, and ONO‐5334‐02) and a study where only trough levels were collected (phase 2 OCEAN study). Design details for the phase 1 studies can be found elsewhere . In the OCEAN study, a total of 285 subjects (57 per treatment group) were randomized to receive placebo, alendronate 70 mg once weekly (QW) or 1 of 3 regimens of ONO‐5334 50 mg BID, 100 mg QD, or 300 mg QD, for 12 months.…”

“…The intra‐ and inter‐assay precision was less than 15% (coefficient of variation), and the intra‐ and inter‐assay accuracy was within 15% of the nominal values for ONO‐5334. The detail of the analytic method can be found elsewhere …”

“…Each study protocol and consent form was reviewed and approved by the investigational review board (IRB)/local ethics committee . All subjects provided written informed consent.…”

“…A two‐compartment PK structural model was selected to describe the PK profile . First‐order, zero‐order, and first‐order plus zero‐order absorption models were assessed.…”

“…Although the percent change from baseline (%CFB) in BMD is a common endpoint in middle to late stages of drug development for osteoporosis, early development commonly includes assessment of bone turnover markers (BTM) in lieu of BMD . The previous population pharmacokinetic–pharmacodynamic (PK–PD) modeling study with bone resorption markers from phase 1 studies showed that ONO‐5334 SRT would provide a comparable PD effect at a lower dose relative to IRT . However it is still unclear which type of PK and/or PD patterns with different formulations would provide ONO‐5334 with the most suitable product profile as an anti‐osteoporosis drug from arguably a better surrogate endpoint of anti‐fracture efficacy, BMD.…”