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Keywords:

  • blood pressure;
  • N-desmethylsildenafil;
  • pharmacokinetics;
  • sildenafil;
  • sitaxentan

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Endothelin-A receptor antagonists (ETRAs) and phosphodiesterase-type 5 inhibitors are approved monotherapies for the treatment of pulmonary arterial hypertension; combining agents from these two drug classes could be beneficial.

• There is a significant pharmacokinetic (PK) interaction between the ETRA bosentan and the phosphodiesterase-type 5 inhibitor sildenafil.

• This study assessed whether the ETRA sitaxentan similarly impacts the PK of sildenafil.

WHAT THIS STUDY ADDS

• This study demonstrates that sitaxentan has little effect on sildenafil PK and pharmacodynamics and that no dose adjustment of either agent is required upon co-administration of sildenafil with sitaxentan.

AIMS This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.

METHODS Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.

RESULTS Sildenafil exposure was slightly higher [AUC geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (Emax+) and maximum negative (Emax–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.

CONCLUSION The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.