Krishna Rajesh, Bergman Arthur J, Jin Bo, Garg Amit, Roadcap Brad, Chiou Rita, Dru James, Cote Josee, Laethem Tine, Wang Regina W, Didolkar Varsha, Vets Eva, Gottesdiener Keith, Wagner John A
Merck Research Laboratories, Mailstop RY34-A500, 126 East Lincoln Avenue, Rahway, NJ 07065-0900, USA.
J Clin Pharmacol. 2009 Jan;49(1):80-7. doi: 10.1177/0091270008326718. Epub 2008 Nov 11.
In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
在本研究中，咪达唑仑被用作探针敏感的CYP3A底物，以研究阿那曲泊帕对CYP3A活性的影响，酮康唑被用作探针抑制剂，以研究强效CYP3A抑制对阿那曲泊帕（一种正在开发用于治疗血脂异常的新型胆固醇酯转运蛋白抑制剂）药代动力学的影响。进行了两项部分盲法、随机、两周期、固定序列研究。评估了安全性、耐受性以及咪达唑仑和阿那曲泊帕的血浆浓度。所有治疗总体耐受性良好。阿那曲泊帕/单独咪达唑仑的咪达唑仑AUC0-无穷大及Cmax的几何平均比值（90%置信区间）分别为1.04（0.94，1.14）和1.15（0.97，1.37）。酮康唑增加了阿那曲泊帕的暴露量——具体而言，阿那曲泊帕与酮康唑/单独阿那曲泊帕的AUC0-无穷大及Cmax的几何平均比值（90%置信区间）分别为4.58（3.68，5.71）和2.37（2.02，2.78）。该研究表明，阿那曲泊帕不抑制或诱导CYP3A活性。此外，阿那曲泊帕似乎是CYP3A的中度敏感底物。
