Burgess Gary, Hoogkamer Hans, Collings Lorraine, Dingemanse Jasper
PGRD, Pfizer Ltd, Sandwich, Kent, UK.
Eur J Clin Pharmacol. 2008 Jan;64(1):43-50. doi: 10.1007/s00228-007-0408-z. Epub 2007 Nov 27.
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 (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.
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.
本研究旨在系统调查磷酸二酯酶-5抑制剂西地那非和双重内皮素受体拮抗剂波生坦在健康志愿者中的相互药代动力学相互作用，这两种药物均被批准用于治疗肺动脉高压（PAH）。
在55名健康男性志愿者（51名完成者）中进行了一项随机、双盲、安慰剂对照、平行组研究，设有三个治疗组（西地那非加安慰剂、波生坦加安慰剂和西地那非加波生坦）。每个治疗组的研究持续时间为18天。西地那非在第1 - 6天和第11 - 16天每日给药三次（初始剂量20mg，3天后增至80mg），波生坦（125mg）在第7 - 17天每日给药两次。
在第16天，波生坦使西地那非的最大血浆浓度（C）（max）降低了55.4% [90%置信区间（CI）40.3 - 66.6%]，并使给药间隔内血浆浓度-时间曲线下面积（AUC）（tau）降低了62.6%（90% CI 56.8 - 67.7%）。西地那非使波生坦的C（max）增加了42.0%（90% CI 15.4 - 74.8%），并使（AUC）（tau）增加了49.8%（90% CI 28.7 - 74.5%）。波生坦和西地那非联合使用耐受性良好，未报告严重不良事件。所有不良事件均为轻度或中度。
在健康志愿者中，波生坦和西地那非之间存在相互药代动力学相互作用，这可能会影响联合治疗中每种药物的剂量。波生坦和西地那非联合治疗的临床意义尚不清楚，需要在PAH患者中进行进一步试验。
