A Population Pharmacokinetic Analysis of Fimasartan, a Selective Angiotensin II Receptor Antagonist, in Healthy Caucasian Subjects and Korean Patients With Hypertension.
A population pharmacokinetic (PK) model of fimasartan, a selective angiotensin II receptor antagonist, was developed and significant covariates for its PK parameters were identified using 1438 plasma concentrations from 69 subjects (aged 19-64 years, weighing 43.5-95.3 kg), enrolled in 2 phase I studies (n = 42, 96.4% Caucasian) and a phase II study (n = 27, Korean hypertensive patients). The nonlinear mixed-effects analysis method by NONMEM was used, and the final model was qualified using sensitivity analysis, bootstrapping, and visual predictive checks. A two-compartment open linear PK model with mixed zero- and lagged first-order absorption best described observed plasma fimasartan concentrations. The typical value of the apparent clearance of fimasartan for those weighing 70 kg with total bilirubin of 0.7 mg/dL was 176 L/h (95% confidence interval: 163-189 L/h), and its interindividual and interoccasion variability as coefficient of variation was 26.9% (20.5-31.6%) and 10.5% (6.3-15.5%), respectively. Simulation of steady state concentrations indicated body weight was the most influential covariate on the exposure of fimasartan (i.e., lower level in heavier subjects). The population PK model of fimasartan should be refined as more studies are conducted in various clinical conditions.
Department of Bioengineering and Therapeutic Sciences, Center for Drug Development Science, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA.|Clinical Trials Center, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Korea.
Howard
H
Lee
Department of Clinical Pharmacology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
In-Jin
IJ
Jang
Department of Clinical Pharmacology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
Kyung-Sang
KS
Yu
R & D Center, Boryung Pharmaceutical Co., Ltd., Seoul, Korea.
Jeongeun
J
Choi
Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
Byung-Hee
BH
Oh
NONMEM; angiotensin receptor antagonist; body weight; fimasartan; hypertension; population pharmacokinetics