title: 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.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Ibaraki, Japan; Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hasegawa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohno
authors.forename: Takeo
authors.initials: T
authors.lastname: Umemura
authors.forename: Naoki
authors.initials: N
authors.lastname: Honda
authors.forename: Michiyo
authors.initials: M
authors.lastname: Ohyama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nagase
authors.forename: Maria
authors.initials: M
authors.lastname: Small
authors.forename: Steve
authors.initials: S
authors.lastname: Deacon
authors.forename: Mikio
authors.initials: M
authors.lastname: Ogawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
mesh_terms: D000368:Aged; D000465:Algorithms; D019540:Area Under Curve; D044466:Asian People; D001835:Body Weight / Q000502:physiology; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005060:Europe; D005260:Female; D006801:Humans; D007564:Japan; D008875:Middle Aged; D015233:Models, Statistical; D017698:Postmenopause / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D053778:Thiazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044465:White People
chemical_list: D015853:Cysteine Proteinase Inhibitors; C560865:ONO-5334; D053778:Thiazolidines; D056657:Cathepsin K
keywords: ONO-5334; biochemical markers of bone turnover; cathepsin K inhibitor; osteoporosis; population pharmacokinetic-pharmacodynamic