title: Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation.
abstract: OBJECTIVE
  This study evaluated if previously published limited sampling models (LSMs) accurately predict midazolam area under the concentration time curve (AUC) during cytochrome P450 (CYP) 3A baseline, inhibition and induction/activation.
  
  
  METHODS
  Plasma midazolam concentrations (n = 108) were obtained where intravenous midazolam was co-administered alone or concomitantly with ketoconazole, itraconazole, aprepitant, rifampin, or pleconaril. Observed AUC was calculated using noncompartmental analysis. Predicted AUC was calculated from the LSMs. Bias and precision were determined by percent mean prediction error (%MPE), percent mean absolute error (%MAE), and percent root mean squared error (%RMSE).
  
  
  RESULTS
  Contrasting results were observed for LSMs in predicting CYP3A baseline activity, with the majority of studies resulting in unacceptable bias and precision. During CYP3A inhibition, unacceptable bias and precision were observed from single- and 2-time point LSMs. %MAE and %RMSE values exceeded acceptable limits during CYP3A induction with rifampin. Contrasting results were observed with pleconaril.
  
  
  CONCLUSIONS
  The contrasting results during CYP3A baseline and induction/activation, as well as the unacceptable bias and precision during CYP3A inhibition, limits the widespread use of the previously published LSMs.
authors.affiliation: University of California, San Diego, CA, USA.
authors.forename: Anh N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Justin T
authors.initials: JT
authors.lastname: Hoffman
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Tsunoda
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
mesh_terms: D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004790:Enzyme Induction; D006801:Humans; D007275:Injections, Intravenous; D008874:Midazolam / Q000494:pharmacology*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam