Stein Evan A, Stroes Erik S G, Steiner George, Buckley Brendan M, Capponi Alessandro M, Burgess Tracy, Niesor Eric J, Kallend David, Kastelein John J P
Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA.
Am J Cardiol. 2009 Jul 1;104(1):82-91. doi: 10.1016/j.amjcard.2009.02.061.
Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.
在另一种胆固醇酯转运蛋白抑制剂托彻普贝（torcetrapib）出现死亡率和心脏事件增加，并伴有脱靶不良反应（高血压和肾素 - 血管紧张素 - 醛固酮系统激活）的报道之后，本文呈现了达塞曲匹（dalcetrapib，RO4607381/JTT - 705）的疗效和安全性数据。在4项为期4周的IIa期联合试验（1项单药治疗，n = 193；3项与他汀类药物联合治疗，n = 353）和1项为期12周的IIb期试验（与普伐他汀联合，n = 292）中，评估了达塞曲匹300 mg、600 mg、900 mg或安慰剂（n = 838）的疗效和临床安全性。通过检测暴露于达塞曲匹或托彻普贝的人肾上腺皮质癌细胞（H295R）中醛固酮生成和醛固酮合酶（细胞色素P450 11B2）信使核糖核酸的诱导情况来评估非临床安全性。达塞曲匹可使高密度脂蛋白胆固醇升高高达36%，载脂蛋白A - I升高高达16%。安慰剂组（42%）、达塞曲匹300 mg组（50%）和600 mg组（42%）的不良事件（AE）发生率相似，达塞曲匹900 mg组的不良事件更多（58%）（p<0.05，汇总的4周研究）。6例严重不良事件（安慰剂组3例，达塞曲匹300 mg组1例，达塞曲匹600 mg组2例）被认为与治疗“无关”。各治疗组的心血管不良事件相似，无剂量相关趋势，血压或心电图结果无临床相关变化。12周研究中的结果相似。在体外，托彻普贝可增加醛固酮生成和细胞色素P450 11B2信使核糖核酸水平，而达塞曲匹则无此作用。总之，达塞曲匹单独使用或与他汀类药物联合使用在升高高密度脂蛋白胆固醇方面有效，且耐受性良好，血压或心血管不良事件无临床相关变化，非临床评估显示对醛固酮生成无影响。
