Authors: Yoshihara, Kazutaka¹; Gao, Yuying²; Shiga, Hiroshi³; Wada, D. Russell²; Hisaoka, Masafumi¹

Source: Clinical Pharmacokinetics, Volume 44, Number 12, 2005 , pp. 1329-1342(14)

Publisher: Adis International

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 μmol/L [approximately 3 mg/dL]) could cause a clearance decrease of ≥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.

Keywords: Angiotensin II 1 receptor antagonists; Antihypertensives; Hypertension; Olmesartan medoxomil; Population pharmacokinetics

Document Type: Research article

Affiliations: 1: 1 Clinical Pharmacology and Biostatistics Department, Sankyo Company Ltd, Shinagawa-ku, Tokyo, Japan 2: 2 Pharsight Corporation, Mountain View, California, USA 3: 3 R&D Project Management Department, Sankyo Company Ltd, Shinagawa-ku, Tokyo, Japan

Publication date: 2005-01-01

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