Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole.
OBJECTIVE
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 t(1/2) 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 t(1/2). 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.


CONCLUSIONS
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.
van Giersbergen
Paul L M
PL
Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 18, 4123 Allschwil, Switzerland. paul.vangiersbergen@actelion.com
Halabi
Atef
A
Dingemanse
Jasper
J
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077300:Bosentan; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D013449:Sulfonamides; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077300:Bosentan; D007654:Ketoconazole