1. Limited Sampling Strategy of Partial Area Under the Concentration–Time Curves to Estimate Midazolam Systemic Clearance for Cytochrome P450 3A Phenotyping
- Author
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Masters, Joanna C, Harano, Denise M, Greenberg, Howard E, Tsunoda, Shirley M, Jang, In-Jin, and D., Joseph
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Adolescent ,Adult ,Area Under Curve ,Cytochrome P-450 CYP3A ,Cytochrome P-450 Enzyme Inhibitors ,Enzyme Induction ,Female ,Humans ,Injections ,Intravenous ,Male ,Midazolam ,Middle Aged ,Phenotype ,Reproducibility of Results ,Specimen Handling ,Young Adult ,CYP3A ,partial AUC ,limited sampling ,midazolam ,phenotyping ,Analytical Chemistry ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences - Abstract
ObjectiveIntravenous (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.MethodsMidazolam 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.ResultsDuring CYP3A baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r(2) ≥ 0.9 and/or percent mean absolute error
- Published
- 2015