1. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.
- Author
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Yoshihara K, Gao Y, Shiga H, Wada DR, and Hisaoka M
- Subjects
- Administration, Oral, Adult, Angiotensin II Type 1 Receptor Blockers blood, Creatinine blood, Europe, Female, Healthy Volunteers, Humans, Imidazoles blood, Japan, Linear Models, Male, Middle Aged, Olmesartan Medoxomil, Retrospective Studies, Tetrazoles blood, United States, Angiotensin II Type 1 Receptor Blockers pharmacokinetics, Hypertension metabolism, Imidazoles pharmacokinetics, Models, Biological, Prodrugs pharmacokinetics, Tetrazoles pharmacokinetics
- 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.
- Published
- 2005
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