The influence of dietary sodium content on the pharmacokinetics and pharmacodynamics of fimasartan

Abstract

A low sodium diet enhances the hemodynamic effect of renin–angiotensin system blockers. It was suggested that the substrates of P-glycoprotein or cytochrome P450 3A4 were reduced on a high sodium diet. This study aimed to investigate the influence of high sodium diet on the pharmacokinetics and pharmacodynamics of fimasartan, which is a substrate of cytochrome P450 3A4 but not P-glycoprotein. The study design was a two-diet, two-period, two-sequence, randomized, open-label, and crossover with 1-week washout for diet. Eligible subjects were fed with either low sodium (50 mEq/day) diet or high sodium diet (300 mEq/day) for 7 days in the first hospitalization period and the other diet in the second period. On the seventh morning of each period, subjects received a single dose of fimasartan 60 mg in a fasted state. The serial plasma concentrations of fimasartan, serum aldosterone concentration (SAC), and plasma renin activity (PRA) were measured for pharmacokinetic–pharmacodynamic analysis. Sixteen subjects completed the study satisfying the compliance test for diets. Although the mean systemic exposure of fimasartan is slightly (≈10%) decreased on a high sodium diet, the difference was not statistically or clinically significant (P>0.05). The SAC and PRA after fimasartan administration were highly dependent on their baseline levels. The dietary sodium content influenced the baseline of SAC and PRA, but did not influence the ratio change of SAC and PRA after fimasartan treatment. The ratio change of SAC after fimasartan treatment was correlated to the systemic exposure of fimasartan (P<0.05), while the correlation between the ratio change of PRA after fimasartan treatment and the individual systemic exposure of fimasartan was not significant (P>0.05). In conclusion, the pharmacokinetics of fimasartan and ratio changes of SAC and PRA after fimasartan treatment were not significantly influenced by dietary sodium content.

Keywords:

• aldosterone
• renin activity
• angiotensin receptor blocker
• aldosterone
• renin
• cytochrome P450 3A4
• P-glycoprotein
• healthy
• sodium diet

Acknowledgments

This study was sponsored by Boryung Pharmaceutical Co., Ltd., Seoul, Republic of Korea. The authors would like to thank Ms. In-Ja Jung, Clinical Trial Center at Dongguk University Ilsan Hospital, who assisted in performing the clinical trial, and Ji Hyun Kim, Department of Pediatrics at Dongguk University Ilsan Hospital, who contributed as a researcher of the clinical trial. The authors do not have stock ownership or patents. There was no financial benefit from the sponsor, including the bonuses based on the success of this drug, and no payment to recruit and treat volunteers.

Disclosure

The authors report no conflicts of interest in this work.