Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

Abstract

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan EC50 in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.