Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin
Authors: Dingemanse J. , Schaarschmidt D. , Van Giersbergen P. L. M. 
Published: March 2003

Bosentan is the first competitive antagonist at endothelin‐A and ‐B receptors that reached the clinic. Endothelin receptor antagonists display a wide spectrum of potential indications. The main indications for which bosentan is currently investigated are pulmonary arterial hypertension and chronic heart failure. Bosentan has a low systemic plasma clearance of approximately 12 l h−1 and a volume of distribution of approximately 0.5 l kg−1. In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP)2C9 and 3A4. The present interaction study was conducted to investigate the mutual pharmacokinetic interactions between bosentan and simvastatin, a substrate of CYP3A4. Inactive simvastatin (lactone form) is biotransformed into the active metabolite β‐hydroxyacid simvastatin. Nine healthy male subjects (age range 24–25 years) were treated in a three‐period randomized crossover study with A) bosentan 125 mg twice daily for 5.5 days; B) simvastatin 40 mg once a day for 6 days; C) bosentan 125 mg twice daily and simvastatin 40 mg once a day for 5.5 and 6 days, respectively. Steady‐state conditions of bosentan and its three identified metabolites were attained by day 4 of treatment, both in the absence and presence of simvastatin co‐administration. In total, the plasma concentrations of the bosentan metabolites were approximately 20% of those of bosentan. Ro 48‐5033, which is a pharmacologically active metabolite, showed an exposure, which was approximately 12% of that to bosentan. The pharmacokinetic parameters (geometric mean with 95% confidence intervals) of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: bosentan values for Cmax in treatment A and C 1006 (768–1318) and 1118 (872–1434) ng ml−1, respectively, and for AUC(0, τ) 4586 (3719–5656) and 4928 (3945–6156) ng ml−1 h, respectively. In contrast, concomitant administration of bosentan resulted in a decreased exposure to simvastatin and β‐hydroxyacid simvastatin. Cmax and AUC(0, τ) values of simvastatin in treatments B and C were 12.9 (8.1–20.5) and 10.7 (7.2–15.9) ng ml−1 and 30.5 (23.1–40.2) and 20.0 (15.9–25.1) ng ml−1 h, respectively. The values for β‐hydroxyacid simvastatin were 7.3 (5.4–9.7) and 6.0 (4.2–8.7) ng ml−1 and 43.0 (32.1–57.8) and 23.4 (16.7–32.6) ng ml−1 h for Cmax and AUC(0, τ) in treatments B and C, respectively. The decrease in exposure to simvastatin and β‐hydroxyacid simvastatin (34 and 46%, respectively) was statistically significant (P<0.05). A trend for a higher incidence of adverse events was observed when bosentan and simvastatin were administered concomitantly, with headache the most frequently reported adverse event. There were no clinically relevant treatment‐related changes in vital signs, ECG or clinical laboratory parameters.

In conclusion, the influence of bosentan on the pharmacokinetics of simvastatin and its metabolite is in accordance with bosentan's enzyme inducing properties. The possibility of reduced efficacy of simvastatin should be considered when administered concomitantly with bosentan.