A population parmacokinetic analysis of fimasartan, a novel angiotensin-receptor antagonist, in healthy subjects and patients with hypertension
Heechan Lee1, 2, Howard Lee1, 2
1Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: 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 (PPK) model of fimasartan and to identify significant covariates that may affect the PPK parameters in healthy subjects and patients with hypertension.
Methods: A total of 4,692 fimasartan plasma concentrations were obtained from 269 subjects enrolled in 11 clinical trials including a first-in-human study, drug-interaction studies, and a proof-of-concept dose-response study. A PPK model was developed using nonlinear mixed-effects modeling analysis methods implemented in NONMEM (ver. 7.30). 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 bootstrapping and visual predictive checks (VPCs).
Results: A two-compartment linear model with mixed zero- and lagged first-order absorption 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 185 L/h (54%), 344 L (89.5%), and 0.459 (107.5%). Covariates such as body weight and age were included in the model. Model evaluation by goodness of fit plots, bootstrapping and VPCs suggested that the proposed model was adequate and robust with good precision.
Conclusions: The final population PK model adequately described the observed plasma concentration of fimasartan in various population groups. Body weight and age were the most significant covariate for the PK parameters of fimasartan.