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.

• Authors: Chihiro Hasegawa, Tomoya Ohno, Takeo Umemura, Naoki Honda, Michiyo Ohyama, Shinichi Nagase, Maria Small, Steve Deacon, Mikio Ogawa, Ichiro Ieiri
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 54 Issue 1 Pg. 23-34 (Jan 2014) ISSN: 1552-4604 [Electronic] England
• PMID: 24115072 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2013, The American College of Clinical Pharmacology.

Chemical References

• Cysteine Proteinase Inhibitors
• ONO-5334
• Thiazolidines
• Cathepsin K

Topics

• Aged
• Algorithms
• Area Under Curve
• Asian People
• Body Weight (physiology)
• Cathepsin K (antagonists & inhibitors)
• Chemistry, Pharmaceutical
• Chromatography, High Pressure Liquid
• Cysteine Proteinase Inhibitors (administration & dosage, pharmacokinetics)
• Dose-Response Relationship, Drug
• Europe
• Female
• Humans
• Japan
• Middle Aged
• Models, Statistical
• Postmenopause (metabolism)
• Tandem Mass Spectrometry
• Thiazolidines (administration & dosage, pharmacokinetics)
• White People