Derks Michael, Fowler Stephen, Kuhlmann Olaf
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Curr Med Res Opin. 2009 Apr;25(4):891-902. doi: 10.1185/03007990902790928.
The primary objective of this study was to investigate the drug-drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone.
Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC(50) for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug-drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5 + 1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed.
In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC(50) values ranged from 1.5 +/- 0.1 microM for CYP2C8 to 82 +/- 4 microM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated.
Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.
本研究的主要目的是采用体外和临床方法，研究达塞曲匹对经主要细胞色素P450（CYP）同工酶代谢的药物的药物相互作用潜力。次要目的是研究达塞曲匹单独使用或与五种探针药物组合或与罗格列酮联合使用时的安全性和耐受性。
使用人肝微粒体和一组CYP酶底物来测定抑制CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4的半数抑制浓度（IC50）。此外，在健康男性中进行了两项药物相互作用研究：达塞曲匹900 mg加库珀斯敦5 + 1药物鸡尾酒（其中包括CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4的底物），以及达塞曲匹900 mg加罗格列酮（一种CYP2C8底物）。评估了药代动力学和安全性参数。
在体外，达塞曲匹对所有测试的CYP酶均有抑制作用。IC50值范围从CYP2C8的1.5±0.1 microM到CYP2D6的82±4 microM。重复给药后，达塞曲匹加药物鸡尾酒联合给药显示900 mg达塞曲匹对CYP1A2、CYP2C19、CYP2D6、CYP2C9或CYP3A4的活性无临床相关影响。达塞曲匹加罗格列酮联合给药显示900 mg达塞曲匹对CYP2C8的活性无临床相关影响。达塞曲匹总体耐受性良好。
尽管体外研究表明达塞曲匹抑制CYP活性，但两项临床研究显示，在900 mg剂量下，对任何主要CYP同工酶均无临床相关影响，该剂量高于III期研究中探索的600 mg剂量。在这些研究中，达塞曲匹总体耐受性良好。然而，这些研究仅限于少数健康男性；需要进行更多、更大规模的研究来研究其安全性。
