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


METHODS
Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan.


METHODS
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.


CONCLUSIONS
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.
Yoshihara
Kazutaka
K
Clinical Pharmacology and Biostatistics Department, Sankyo Company Ltd, Shinagawa-ku, Tokyo, Japan. kyoshi@sankyo.co.jp
Gao
Yuying
Y
Shiga
Hiroshi
H
Wada
D Russell
DR
Hisaoka
Masafumi
M
D000284:Administration, Oral; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D005060:Europe; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D007564:Japan; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000068557:Olmesartan Medoxomil; D011355:Prodrugs / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics*; D014481:United States
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011355:Prodrugs; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; C437965:olmesartan; D003404:Creatinine