Assessment of oral midazolam limited sampling strategies to predict area under the concentration time curve (AUC) during cytochrome P450 (CYP) 3A baseline, inhibition and induction or activation

J. D. Ma, E. T. Nguyen, S. M. Tsunoda, H. E. Greenberg, J. C. Gorski, S. R. Penzak, L. S. Lee

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

A previous study reported a 2-and 3-timepoint limited sampling strategy (LSS) model accurately predicted oral midazolamarea under the concentration time curve (AUC), and thus cytochrome P450 (CYP) 3A activity. Objective: This study evaluated whether the LSS models predict midazolam AUC during CYP3A baseline, inhibition and induction/activation. Materials and methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)847-853
Number of pages7
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume48
Issue number12
DOIs
StatePublished - Dec 2010

Keywords

  • CYP3A
  • Limited sampling strategy
  • Midazolam
  • Phenotyping

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