Ma J D, Nguyen E T, Tsunoda S M, Greenberg H E, Gorski J C, Penzak S R, Lee L S
University of California, San Diego (UCSD), Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093-0714, USA.
Int J Clin Pharmacol Ther. 2010 Dec;48(12):847-53. doi: 10.5414/cpp48847.
A previous study reported a 2- and 3-timepoint limited sampling strategy (LSS) model accurately predicted oral midazolam area under the concentration time curve (AUC), and thus cytochrome P450 (CYP) 3A activity.
This study evaluated whether the LSS models predict midazolam AUC during CYP3A baseline, inhibition and induction/activation.
Plasma midazolam concentrations from 106 healthy adults from 6 published studies were obtained where oral midazolam was co-administered alone or with ketoconazole, double-strength grapefruit juice, Ginkgo biloba extract, pleconaril, or rifampin. Observed and predicted midazolam AUCs were determined. Bias and precision of the LSS models were determined.
Contrasting results were observed for the 2- and 3-timepoint LSS models in accurately predicting midazolam AUC during baseline CYP3A conditions. With the exception of 1 study (single dose, double-strength grapefruit juice), the 2- and 3-timepoint LSS models did not accurately predict midazolam AUC during conditions of CYP3A inhibition and induction/activation.
The previously reported 2- and 3-timepoint oral midazolam LSS models are not applicable to the evaluated conditions of CYP3A baseline, inhibition, and induction/ activation.
先前的一项研究报告称，一种两时间点和三时间点的有限采样策略（LSS）模型能够准确预测咪达唑仑的血药浓度-时间曲线下面积（AUC），进而预测细胞色素P450（CYP）3A活性。
本研究评估LSS模型是否能预测CYP3A基线、抑制及诱导/激活状态下咪达唑仑的AUC。
从6项已发表研究中获取了106名健康成年人的血浆咪达唑仑浓度，这些研究中口服咪达唑仑单独给药或与酮康唑、双倍浓度葡萄柚汁、银杏叶提取物、普来可那立或利福平联合给药。测定了观察到的和预测的咪达唑仑AUC。确定了LSS模型的偏差和精密度。
在准确预测CYP3A基线条件下咪达唑仑的AUC时，两时间点和三时间点的LSS模型得到了不同的结果。除1项研究（单剂量、双倍浓度葡萄柚汁）外，两时间点和三时间点的LSS模型在CYP3A抑制及诱导/激活条件下均未准确预测咪达唑仑的AUC。
先前报道的两时间点和三时间点口服咪达唑仑LSS模型不适用于所评估的CYP3A基线、抑制及诱导/激活条件。
