Limited Sampling Strategy of Partial Area Under the Concentration-Time Curves to Estimate XXXX Systemic Clearance for Cytochrome P450 3A Phenotyping.

@entity5322 @entity1363
OBJECTIVE:: Intravenous (IV) @entity1363 is the preferred cytochrome P450 (CYP) 3A probe for phenotyping, with systemic clearance (CL) estimating hepatic @entity5322 activity. A limited sampling strategy was conducted to determine whether partial area under the concentration-time curves (AUCs) could reliably estimate @entity1363 systemic CL during conditions of @entity5322 baseline activity, inhibition, and induction/activation. METHODS:: @entity1363 plasma concentrations during @entity5322 baseline (n = 93), inhibition (n = 40), and induction/activation (n = 33) were obtained from 7 studies in healthy adults. Noncompartmental analysis determined observed CL (CLobs) and partial AUCs. Linear regression equations were derived from partial AUCs to estimate CL (CLpred) during @entity5322 baseline, inhibition, and induction/activation. Preestablished criterion for linear regression analysis was r >=  0.9. CLpred was compared with CLobs, and relative bias and precision were assessed using percent mean prediction error and percent mean absolute error. RESULTS:: During @entity5322 baseline and inhibition, all evaluated partial AUCs failed to meet criterion of r >=  0.9 and/or percent mean absolute error <15%. During @entity5322 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 @entity5322 induction/activation, but not baseline or inhibition, @entity1363 partial AUC0-1, AUC0-2, and AUC0-4 reliably estimated systemic CL and consequently hepatic @entity5322 activity in healthy adults.
