Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.
BACKGROUND
In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4.


OBJECTIVE
To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate.


METHODS
Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6.


RESULTS
Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively.


CONCLUSIONS
Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.
Dingemanse
Jasper
J
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. jasper.dingemanse@actelion.com
Schaarschmidt
Dieter
D
van Giersbergen
Paul L M
PL
D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D000077300:Bosentan; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077300:Bosentan