Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil.
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 (c)(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 (AUC(tau)) by 62.6% (90% CI 56.8-67.7%). Sildenafil increased bosentan C(max) by 42.0% (90% CI 15.4-74.8%) and (AUC(tau)) 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.
PGRD, Pfizer Ltd, Sandwich, Kent, UK. Gary.Burgess@pfizer.com
Gary
G
Burgess
Hans
H
Hoogkamer
Lorraine
L
Collings
Jasper
J
Dingemanse
D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D000077300:Bosentan; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D011651:Pulmonary Artery; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D000077300:Bosentan