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Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

Abstract：

BACKGROUND:Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. OBJECTIVE:To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. DESIGN:Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. PARTICIPANTS:Eighty-nine healthy volunteers and 383 hypertensive patients. METHODS:Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. RESULTS:The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. CONCLUSION:The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Yoshihara K,Gao Y,Shiga H,Wada DR,Hisaoka M

doi

10.2165/00003088-200544120-00011

keywords:

subject

Has Abstract

pub_date

2005-01-01 00:00:00

pages

1329-42

issue

eissn

0312-5963

issn

1179-1926

pii

441211

journal_volume

pub_type

杂志文章,meta分析

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Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.