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J Clin Pharmacol. 2014 Jan;54(1):23-34. doi: 10.1002/jcph.186. Epub 2013 Oct 10.

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

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1
Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki, Japan; Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

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.

KEYWORDS:

ONO-5334; biochemical markers of bone turnover; cathepsin K inhibitor; osteoporosis; population pharmacokinetic-pharmacodynamic

PMID:
24115072
DOI:
10.1002/jcph.186
[Indexed for MEDLINE]
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