Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques

Abstract

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.

Ketoconazole Renders Poor CYP3A Phenotype Status With Midazolam as Probe Drug

“…Earlier studies by various groups, including our own, established LSS for midazolam AUC mainly in the uninhibited state of CYP3A4. 9,36 The only other study that examined the use of LSS for midazolam in an inhibited as well as induced states for CYP 3A reported the successful use of a single time point at 4 hours, close to the harmonic mean of the MRT, 3.5 hours. 8 Although the harmonic mean of the MRT may be a good guide for the selection of an optimal sampling time for single-point LSS based on statistical moment theory, the case was different in this study.…”

Limited sampling strategy in rats to predict the inhibited activities of hepatic CYP3A

“…LSS has been used to estimate pharmacokinetic parameters for therapeutic agents 9 -11 or to monitor the drug administration regimen, 12,13 and also to predict CYP3A activity using a phenotyping probe drug. 9,14 However, it is still unclear whether the predictive equation for MDZ clearance using a LSS generated from a randomized population in which Laboratory Animals 2009; 43: 284 -290 hepatic CYP3A may have been inhibited to varying degrees could be used to estimate CYP3A-dependent metabolism in the rat liver. Resolving this question is a valuable contribution to metabolism research.…”

S-Warfarin Limited Sampling Models to Estimate Area Under the Concentration Versus Time Curve for Cytochrome P450 2C9 Baseline Activity and After Induction

“…20 In contrast, another study evaluated IV midazolam LSMs and reported acceptable precision and bias when comparing LC/MS/ MS and electron capture gas chromatography assays. 17 Consequently, the magnitude and extent to which different bioanalytical assays contribute to findings in this study is unknown but may provide a partial explanation for our findings.…”

“…Bias and precision were assessed by acceptable limits of percent mean prediction error (%MPE) 25 to 5%, percent mean absolute error (%MAE) # 10%, and percent root mean square error (%RMSE) # 15%. 4,16,17 …”