Jaeseong Oh, MD, Jongtae Lee, MD, In-Jin Jang MD, PhD, and Howard Lee, MD, PhD
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: Fimasartan is a novel nonpeptide angiotensin II receptor antagonist with a selective AT1 receptor blockade effect. The objective of this study was to develop a population pharmacokinetic (PK) – pharmacodynamic (PD) model, which can adequately describe and predict the PK-PD profiles of fimasartan in patients with mild to moderate hypertension.
Methods: A total of 1,438 fimasartan plasma concentrations and 759 clinic blood pressure measurements from 42 healthy subjects and 59 patients with mild to moderate essential hypertension (assigned to one of the following dose groups: placebo, 20 mg, 60 mg and 180 mg) were pooled to develop a population PK-PD model using the nonlinear mixed-effects method in NONMEM (ver. Ⅵ).
Results: A two-compartment open linear model with mixed zero- and first- order absorptions and firs-order elimination as the final PK model. The typical values of apparent clearance (CL/F), apparent central volume of distribution (V2/F) and fraction absorbed via first-order process (F1) were 176 L/h, 371 L and 56.4%, respectively.
The final PK-PD model was a random baseline effect compartment Emax model with placebo response. The equilibrium constants for the effect compartment were 0.052 and 0.0263 hr-1 for DBP and SBP, respectively. The maximum blood pressure reduction effects were estimated to be 20.9 and 38.8 mmHg for DBP and SBP, respectively. The plasma concentrations at 50% of maximum effect were 23.3 and 30.2 ng/mL for DBP and SBP, respectively.
Conclusions: The final PK-PD model of fimasartan adequately described the observed blood pressure profiles in patients with mild to moderate hypertension. The model developed in this study could be applied in guiding further clinical development of fimasartan.
Reference: PAGE 22 (2013) Abstr 2733 [www.page-meeting.org/?abstract=2733]
Poster: Other Drug/Disease Modelling