Background: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4.
Purpose: 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.