title: Limited sampling strategy of partial area under the concentration-time curves to estimate midazolam systemic clearance for cytochrome P450 3A phenotyping.
abstract: OBJECTIVE
  Intravenous (IV) midazolam is the preferred cytochrome P450 (CYP) 3A probe for phenotyping, with systemic clearance (CL) estimating hepatic CYP3A activity. A limited sampling strategy was conducted to determine whether partial area under the concentration-time curves (AUCs) could reliably estimate midazolam systemic CL during conditions of CYP3A baseline activity, inhibition, and induction/activation.
  
  
  METHODS
  Midazolam plasma concentrations during CYP3A baseline (n = 93), inhibition (n = 40), and induction/activation (n = 33) were obtained from 7 studies in healthy adults. Noncompartmental analysis determined observed CL (CL(obs)) and partial AUCs. Linear regression equations were derived from partial AUCs to estimate CL (CL(pred)) during CYP3A baseline, inhibition, and induction/activation. Preestablished criterion for linear regression analysis was r(2) ≥ 0.9. CL(pred) was compared with CL(obs), and relative bias and precision were assessed using percent mean prediction error and percent mean absolute error.
  
  
  RESULTS
  During CYP3A baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r(2) ≥ 0.9 and/or percent mean absolute error <15%. During CYP3A induction/activation, equations derived from partial AUCs from 0 to 1 hour (AUC0-1), 0 to 2 hours (AUC0-2), and 0 to 4 hours (AUC0-4) were acceptable, with good precision and minimal bias. These equations provided the same conclusions regarding equivalency testing compared with intense sampling.
  
  
  CONCLUSIONS
  During CYP3A induction/activation, but not baseline or inhibition, midazolam partial AUC0-1, AUC0-2, and AUC0-4 reliably estimated systemic CL and consequently hepatic CYP3A activity in healthy adults.
authors.affiliation: *Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla; †Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA; and ‡Seoul National University College of Medicine, South Korea.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Masters
authors.forename: Denise M
authors.initials: DM
authors.lastname: Harano
authors.forename: Howard E
authors.initials: HE
authors.lastname: Greenberg
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: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D010641:Phenotype; D015203:Reproducibility of Results; D013048:Specimen Handling; D055815:Young Adult
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam