Bosentan modestly decreases ciclosporin levels,and ciclosporinincreases bosentan levels. The manufacturer of bosentan contraindicates combination, because of possible increasedrisk of liver toxicity.
Clinical evidence,mechanism, importance and management
In a study designed to assess effects of bosentan on ciclosporin renal toxicity, 7 healthy subjects were given bosentan 500mg and ciclosporin 300 mg, both twice daily, for 7 days. Bosentan did maintain renal plasma flow,which is markedly decreased by ciclosporin. However, bosentan was calculated to have reduced AUC of ciclosporin by about 50%. In addition, bosentan had no effect on ciclosporin-induced rise in blood pressure, and headache, nausea, and vomiting were a problem with combination. Moreover, steady-state AUC of bosentan was raised 1.7-fold when compared with AUC of a single dose of bosentan (See reference number 1). It should be noted that bosentan induces its own metabolism,and after 7 days, plasma levels are about 50 to 65 % of those seen after a single dose (See reference number 2). Therefore, effect of ciclosporin on bosentan AUC may be twice those described in this study (i.e. up to a fourfold increase in AUC of bosentan). The manufacturers of bosentan say that when bosentan is given with ciclosporin its plasma levels were markedly raised (30-fold after a single dose and three- to fourfold at steady state). They also list ciclosporin as an example of a drug, like bosentan, that inhibits bile salt export pump, and is therefore expected to increase risk of liver toxicity when used with bosentan. They therefore contraindicate combination (See reference number 2). Further study is needed, as some consider combination to have clinical potential.
The combination of tacrolimus or sirolimus with bosentan has not been studied but based on information available for ciclosporin, manufacturers of bosentan advise against concurrent use, but if it is required, close monitoring is recommended (See reference number 2).
Binet I,Wallnöfer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmacokineticsof bosentan with and without cyclosporine A. Kidney Int (2000) 57, 224–31.
Tracleer (Bosentan monohydrate). Actelion Pharmaceuticals UK. UK Summary of productcharacteristics,October 2006.