Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, 69120, Heidelberg, Germany.
J Clin Pharmacol. 2013 Nov;53(11):1199-204. doi: 10.1002/jcph.161. Epub 2013 Aug 31.
This study aimed to demonstrate that the dose of a CYP3A substrate (simvastatin) can be adapted individually on the basis of CYP3A activity as assessed by midazolam metabolic clearance. In 18 healthy participants individual CYP3A activity was quantified using midazolam metabolic clearance both alone and during CYP3A inhibition with 40 mg ritonavir. Thereafter, simvastatin acid exposure was determined after a simvastatin standard dose (40 mg) and doses adapted to individual CYP3A activity at baseline and during CYP3A inhibition. Interindividual variability of CYP3A activity and simvastatin acid AUC0-24 was large and both correlated (r(2) = 0.745, P < .001). The adapted simvastatin doses ranged from 25 to 80 mg and their administration reduced simvastatin variability fivefold. Despite the low adapted simvastatin dose of 12 mg during CYP3A inhibition with ritonavir, exposure increased (point estimate of 4.2 [90% CI: 3.15-5.61]) probably caused by additional OATP1B1 inhibition. CYP3A activity-based dose adaptation can be used to reduce interindividual variability in simvastatin exposure.
本研究旨在证明，基于咪达唑仑代谢清除率评估的 CYP3A 活性，可以对 CYP3A 底物（辛伐他汀）的剂量进行个体化调整。在 18 名健康参与者中，单独使用咪达唑仑代谢清除率和 CYP3A 抑制时使用 40mg 利托那韦来定量个体 CYP3A 活性。此后，在辛伐他汀标准剂量（40mg）和基线时以及 CYP3A 抑制时根据个体 CYP3A 活性调整的剂量后，确定辛伐他汀酸暴露量。CYP3A 活性和辛伐他汀酸 AUC0-24 的个体间变异性较大，且两者均相关（r(2) = 0.745，P < .001）。调整后的辛伐他汀剂量范围为 25 至 80mg，其给药使辛伐他汀的变异性降低了五倍。尽管在利托那韦抑制时使用 12mg 的低剂量调整后的辛伐他汀，但暴露量增加（点估计值为 4.2[90%CI：3.15-5.61]），可能是由于额外的 OATP1B1 抑制所致。基于 CYP3A 活性的剂量调整可用于降低辛伐他汀暴露的个体间变异性。
