Limited Sampling Strategy of Partial Area Under the Concentration-Time Curves to Estimate Midazolam Systemic Clearance for Cytochrome P450 3A Phenotyping

作者：Masters Joanna C; Harano Denise M; Greenberg Howard E; Tsunoda Shirley M; Jang In Jin; Ma Joseph D^*

来源：Therapeutic Drug Monitoring, 2015, 37(1): 84-89.

DOI：10.1097/FTD.0000000000000116

• CYP3A
• partial AUC
• limited sampling
• midazolam
• phenotyping

Objective: Intravenous (IV) midazolam is the preferred cytochrome P450 (CYP) 3A probe for phenotyping, with systemic clearance (CL) estimating hepatic CYP3A activity. A limited sampling strategy was conducted to determine whether partial area under the concentration-time curves (AUCs) could reliably estimate midazolam systemic CL during conditions of CYP3A baseline activity, inhibition, and induction/activation.
Methods: Midazolam plasma concentrations during CYP3A baseline (n = 93), inhibition (n = 40), and induction/activation (n = 33) were obtained from 7 studies in healthy adults. Noncompartmental analysis determined observed CL (CLobs) and partial AUCs. Linear regression equations were derived from partial AUCs to estimate CL (CLpred) during CYP3A baseline, inhibition, and induction/activation. Preestablished criterion for linear regression analysis was r(2) >= 0.9. CLpred was compared with CLobs, and relative bias and precision were assessed using percent mean prediction error and percent mean absolute error.
Results: During CYP3A baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r(2) >= 0.9 and/or percent mean absolute error <15%. During CYP3A induction/activation, equations derived from partial AUCs from 0 to 1 hour (AUC(0-1)), 0 to 2 hours (AUC(0-2)), and 0 to 4 hours (AUC(0-4)) were acceptable, with good precision and minimal bias. These equations provided the same conclusions regarding equivalency testing compared with intense sampling.
Conclusions: During CYP3A induction/activation, but not baseline or inhibition, midazolam partial AUC(0-1), AUC(0-2), and AUC(0-4) reliably estimated systemic CL and consequently hepatic CYP3A activity in healthy adults.

• 出版日期2015-2