Abstract

Objective: Avosentan is a potent, selective endothelin A receptor blocker. The effect of food intake on the pharmacokinetics of avosentan was investigated in healthy volunteers. Methods: 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. Results: The overall exposure to avosentan and its metabolite, as reflected by the area under the plasma concentration-time curve from time zero to infinity (AUC_0-µ), was not affected by food intake. The ratios of least square means (90% confidence interval (CI)) of AUC_0-µ 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 (C_max) of avosentan and its metabolite was increased by food intake, and their apparent terminal half-life (t_1/2) 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 C_max 1.61 (1.37, 1.90) and 1.46 (1.27, 1.67), and t_1/2 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. Conclusion: Food intake does not influence the pharmacokinetics of avosentan to a clinically relevant extent.

Author Details

Authors

• W. Dieterle¹
• T. Hengelage²

Departments

• ¹ Drug Disposition Consultants, Loerrach, Germany, and
• ² Clinical Research and Development, Speedel Pharma AG, Basel, Switzerland

Address

Dr. T. Hengelage; Speedel Pharma AG, Department of Clinical Research & Development, Hirschgässlein 11, 4051 Basel, Switzerland
Email: [email protected]

Citation