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

Wei Tai, Sheryl L. Gong, Shirley M. Tsunoda, Howard E. Greenberg, J. Christopher Gorski, Scott R. Penzak, S. Aubrey Stoch, Joseph D. Ma

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: Midazolam apparent oral clearance (CLORAL) 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 CLORAL. 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 CLORAL and partial AUCs of AUC 0-2, AUC0-4, AUC0-6, AUC1-2, AUC1-4, 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 CLORAL 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 CLORAL equations had unacceptable %MAE. Acceptable r2, %MPE, and %MAE were observed during CYP3A induction/activation with AUC0-4 (r2 = 0.99, %MPE = 3.9, %MAE = 12.5) and AUC1-4 (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 AUC0-4 and AUC1-4. Conclusions: Midazolam partial AUCs were unable to estimate CYP3A activity during the evaluated baseline and inhibitory conditions. Midazolam CL ORAL utilizing a partial AUC0-4 and AUC1-4 was able to estimate CYP3A induction with rifampin and Ginkgo biloba extract.

Original languageEnglish
Pages (from-to)217-223
Number of pages7
JournalDrug Metabolism and Drug Interactions
Volume28
Issue number4
DOIs
StatePublished - 1 Dec 2013

Keywords

  • cytochrome P450 3A (CYP3A)
  • limited sampling
  • midazolam
  • partial AUC
  • phenotyping

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