The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects.
BACKGROUND
* 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.


CONCLUSIONS
* 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.


OBJECTIVE
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(infinity) 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 (E(max)+) and maximum negative (E(max)-) 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.


CONCLUSIONS
The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.
Stavros
Fiona
F
Encysive Pharmaceuticals, Department of Medical Information, Houston, TX, USA. fstavros@cox.net
Kramer
William G
WG
Wilkins
Martin R
MR
D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000493:pharmacokinetics* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013876:Thiophenes; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; C106276:sitaxsentan