Pharmacokinetics and Disposition

European Journal of Clinical Pharmacology

, Volume 64, Issue 1, pp 43-50

First online:

Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil

  • Gary BurgessAffiliated withPGRD, Pfizer Ltd Email author 
  • , Hans HoogkamerAffiliated withActelion Pharmaceuticals Ltd
  • , Lorraine CollingsAffiliated withPGRD, Pfizer Ltd
  • , Jasper DingemanseAffiliated withActelion Pharmaceuticals Ltd

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Abstract

Objective

The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH).

Methods

A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17.

Results

On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ©max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval \( {\left( {{\text{AUC}}_{\tau } } \right)} \) by 62.6% (90% CI 56.8–67.7%). Sildenafil increased bosentan Cmax by 42.0% (90% CI 15.4–74.8%) and \( {\left( {{\text{AUC}}_{\tau } } \right)} \) by 49.8% (90% CI 28.7–74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity.

Conclusions

In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.

Keywords

Bosentan Combination therapy Pharmacokinetics Sildenafil