BackgroundOlmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1receptor subtype.ObjectiveTo 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.DesignRetrospective analysis of data from 12 phase I–III trials in the US, Europe and Japan.ParticipantsEighty-nine healthy volunteers and 383 hypertensive patients.MethodsNonlinear 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.ResultsThe 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.ConclusionThe 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.