title: Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping.
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 AUC0-2, 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 CLORAL 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 CLORAL utilizing a partial AUC0-4 and AUC1-4 was able to estimate CYP3A induction with rifampin and Ginkgo biloba extract.
authors.forename: Wei
authors.initials: W
authors.lastname: Tai
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Gong
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Tsunoda
authors.forename: Howard E
authors.initials: HE
authors.lastname: Greenberg
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Gorski
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D015982:Bias; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D010641:Phenotype; D012044:Regression Analysis; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D006993:Hypnotics and Sedatives; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam