Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

Background: Midazolam apparent oral clearance (CL_ORAL) is used to estimate intestinal and hepatic cytochrome P450 (CYP) 3A activity. A limited sampling approach was performed to access a midazolam partial area under the concentration time curve (AUC) to estimate CL_ORAL. Methods: Midazolam plasma concentrations from healthy adults were obtained during CYP3A baseline (n = 116), inhibition (n = 75), and induction or activation (n = 66) from seven published studies. Observed CL_ORAL and partial AUCs of AUC _0-2, AUC_0-4, AUC0-6, AUC1-2, AUC_1-4, AUC2-4, and AUC2-6 were determined by noncompartmental analysis. Subject data were randomly divided into a training set and a validation set. Linear regression equations, derived from partial AUCs, were developed from training set data. Predicted CL_ORAL was determined from these equations from validation set data. Preset criterion was a coefficient of determination (r2) greater than or equal to 0.9. Bias and precision were evaluated by relative percent mean prediction error (%MPE) and relative percent mean absolute error (%MAE). Results: During CYP3A baseline conditions, all of the evaluated CL _ORAL equations had unacceptable r2 (range: 0.34 0.86). During CYP3A inhibition, all of the evaluated CL_ORAL equations had unacceptable %MAE. Acceptable r2, %MPE, and %MAE were observed during CYP3A induction/activation with AUC_0-4 (r² = 0.99, %MPE = 3.9, %MAE = 12.5) and AUC_1-4 (r² = 0.99, %MPE = 6%, %MAE = 11.1%). The same equations also predicted the extent of CYP3A induction as a lack of equivalence was observed with AUC_0-4 and AUC_1-4. Conclusions: Midazolam partial AUCs were unable to estimate CYP3A activity during the evaluated baseline and inhibitory conditions. Midazolam CL _ORAL utilizing a partial AUC_0-4 and AUC_1-4 was able to estimate CYP3A induction with rifampin and Ginkgo biloba extract.