Article date: June 2002
By: Paul L. M. van Giersbergen, Atef Halabi, Jasper Dingemanse, in Volume 53, Issue 6, pages 589-595
Aims The present study was conducted to characterize the single‐ and multiple‐dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole.
Methods In a randomized, two‐way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B.
Results Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5–6.0 h) and a t½ of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t½. Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1‐ (95% CI; 1.5, 2.7) and 2.3‐fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited.
Discussion The multiple‐dose pharmacokinetics of bosentan are consistent with the phenomenon of auto‐induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2‐fold.
DOI: 10.1046/j.1365-2125.2002.01608.x
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