Influence of food intake on the pharmacokinetics of avosentan in man.
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 (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.


CONCLUSIONS
Food intake does not influence the pharmacokinetics of avosentan to a clinically relevant extent.
Dieterle
W
W
Drug Disposition Consultants, Loerrach, Germany.
Hengelage
T
T
D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
D004041:Dietary Fats; D065130:Endothelin A Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; C519554:Ro 68-5925; C484919:Avosentan