European Journal of Clinical Pharmacology

, Volume 64, Issue 1, pp 43–50 | Cite as

Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil

  • Gary Burgess
  • Hans Hoogkamer
  • Lorraine Collings
  • Jasper Dingemanse
Pharmacokinetics and Disposition



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).


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.


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.


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.


Bosentan Combination therapy Pharmacokinetics Sildenafil 



The authors acknowledge that editorial assistance was provided by Mukund Nori, PhD, MBA, Envision Pharma, Inc. in the preparation of this manuscript and that funding was provided by Pfizer, Inc.

Conflict of interest statement

G. Burgess and L. Collings are employees of Pfizer Ltd. J. Dingemanse and H. Hoogkamer are employees of Actelion Pharmaceuticals Ltd. This study was supported by Pfizer Ltd and by Actelion Pharmaceuticals Ltd.


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Gary Burgess
    • 1
  • Hans Hoogkamer
    • 2
  • Lorraine Collings
    • 1
  • Jasper Dingemanse
    • 2
  1. 1.PGRD, Pfizer LtdSandwichUK
  2. 2.Actelion Pharmaceuticals LtdAllschwilSwitzerland

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