A population pharmacokinetic analysis of fimasartan, a novel angiotensin-receptor antagonist, in healthy subjects and patients with hypertension

Abstract

Introduction: Fimasartan is a newly developed antihypertensive agent that selectively blocks the type 1 angiotensin II receptor. The objectives of this study were to develop a population pharmacokinetic (PK) model of fimasartan and to identify significant covariates that may affect the population PK parameters in healthy subjects and patients with hypertension.

Method: A total of 3,978 fimasartan plasma concentrations were obtained from 268 subjects enrolled in 11 clinical trials including a first-in-human study, drug-interaction studies, and a proof-of-concept dose-response study. A population PK model was developed using nonlinear mixed-effects modeling analysis methods implemented in NONMEM (ver. 7.40). The iterative-two stage, Stochastic Approximation Expectation-Maximization and Monte-Carlo Importance Sampling assisted by mode a posteriori estimation with mu-referencing were implemented, which was followed by model qualification using goodness of fit plots and visual predictive checks (VPCs).

Results: A two-compartment linear model with mixed absorption (zero- + first-order), lag time and first-order elimination adequately described plasma fimasartan concentration. A proportional error models were used to account for remained intra-subject variability. The typical values of population PK parameters (inter-individual variability, CV%) of apparent clearance, apparent central volume of distribution, and fraction absorbed via first-order process was 159 L/h (53.7%), 371 L (71.8%), and 0.367 (114.6%). Covariates such as body weight and age were included in the model. Model evaluation by goodness of fit plots and VPCs suggested that the proposed model was adequate and robust with good precision.

Discussion: The final population PK model adequately described the observed plasma concentration of fimasartan in various population groups. Body weight and hepatic impairment status were selected as significant covariate of the final population PK model for fimasartan.