Influence of food intake on the pharmacokinetics of avosentan in man

Abstract

Avosentan is a potent, selective endothelin A receptor blocker. The effect of food intake on the pharmacokinetics of avosentan was investigated in healthy volunteers. In a randomized, open-label, 2-period oral crossover study, 12 healthy subjects (8 males and 4 females) received Treatments A and B. Treatment A consisted of a single dose of avosentan 50 mg after a high-fat, high-calorie breakfast. Treatment B consisted of a single dose of avosentan 50 mg administered in the fasted state. Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. The overall exposure to avosentan and its metabolite, as reflected by the area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), was not affected by food intake. The ratios of least square means (90% confidence interval (CI)) of AUC0-inf for avosentan and Ro 68-5925 in the fed and fasted state were 1.06 (0.96, 1.17) and 1.05 (0.96, 1.15), respectively. The maximum plasma concentration (Cmax) of avosentan and its metabolite was increased by food intake, and their apparent terminal half-life (t1/2) was shortened. The ratios of least square means (90% CI) of pharmacokinetic parameters for avosentan and its metabolite in the fed and fasted state were Cmax 1.61 (1.37, 1.90) and 1.46 (1.27, 1.67), and t1/2; 0.80 (0.69, 0.92) and 0.61 (0.51, 0.74), respectively. Single oral doses of avosentan were well tolerated under fasted and fed conditions. Food intake does not influence the pharmacokinetics of avosentan to a clinically relevant extent.