Dingemanse Jasper, Nicolas Laurent B, van Bortel Luc
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland,
Eur J Clin Pharmacol. 2014 Jun;70(6):675-84. doi: 10.1007/s00228-014-1674-1. Epub 2014 Apr 15.
ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties.
Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study.
Exposure (as based on area under the curve) to simvastatin and 6β-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6β-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41.
This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.
将直接肾素抑制剂ACT-178882用作模型化合物，与阿托伐他汀和辛伐他汀进行详细的药物相互作用研究，以探索复杂的CYP3A4诱导和抑制特性。
32名健康男性受试者在第1、9、31和41天接受单剂量的20 mg阿托伐他汀和20 mg辛伐他汀。在第6至33天，每天一次给予500 mg ACT-178882。通过液相色谱-串联质谱法测定ACT-178882、辛伐他汀和阿托伐他汀的血浆浓度。在整个研究过程中进行常规安全性评估。
与第1天相比，第9天时辛伐他汀及其6β-羟基酸代谢物的暴露量（基于曲线下面积）分别增加了4.63倍（90%置信区间：3.90, 5.50）和3.71倍（3.19, 4.32）。在第9天，阿托伐他汀的暴露量相似，但Cmax降低，而与第1天相比，邻羟基阿托伐他汀的两个变量均降低。在第31天，长期给予ACT-178882后，与第9天相比，阿托伐他汀、邻羟基阿托伐他汀、辛伐他汀和6β-羟基酸辛伐他汀的暴露量分别降低了14%、19%、21%和27%。然而，在这一天，与第1天相比，辛伐他汀及其代谢物的暴露量仍然明显更高。在第41天，ACT-178882的作用已基本消失。
该设计能够利用临床相关底物研究对CYP3A4活性复杂的时间依赖性影响。
