Proposal of a new limited sampling strategy to predict CYP3A activity using a partial AUC of midazolam

Abstract

International audienc

Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

“…The CL ORAL equations derived from AUC 0-4 and AUC 1-4 during CYP3A induction/activation conditions are somewhat consistent with previous studies recommending use of a partial AUC to estimate metabolic clearance and thus CYP3A activity [26,27]. However, the recommended partial AUC varied between studies as Katzenmaier et al recommended an AUC 2-4 as the best independent variable to estimate metabolic clearance [26].…”

“…In addition, one study used for the data analysis had the last midazolam concentration collected at 6 h post dose during CYP3A baseline conditions and limited the evaluation of later partial AUCs [5]. Partial AUCs were dose normalized to 1 mg as midazolam doses differed for each study (Table 1) [26,27]. Partial AUCs were then log-transformed to obtain a normal distribution prior to analyses [28].…”

“…Partial AUCs were selected based on the previous studies of partial AUCs that evaluated timepoint "zero" for the P-glycoprotein probe, digoxin [25], and reported partial AUCs of AUC 1-2 , AUC 1-4 , AUC 2-4 , and AUC 1-6 with midazolam [26]. In addition, one study used for the data analysis had the last midazolam concentration collected at 6 h post dose during CYP3A baseline conditions and limited the evaluation of later partial AUCs [5].…”

Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity

“…In both study phases, participants received 3×300 mg St John's wort [JARSIN ® dragée, LI 160; Casella-med GmbH & Co., Cologne, Germany] over 8 days (day 2 until day 9). To assess CYP3A activity, midazolam exposure was determined using a limited sampling strategy after the oral administration of 3 mg midazolam (Dormicum ® V 5 mg/5 mL solution for injection; Roche, Grenzach-Wyhlen, Germany) using four blood samples drawn at 2, 2.5, 3, and 4 h after administration [10,11]. Midazolam clearance was measured at baseline (day 1), after co-administration of ketoconazole and St John's wort (day 9) and after their discontinuation (days 10, 11 and 12).…”

“…5.03 (GraphPad Software, La Jolla, CA). Midazolam partial metabolic clearance was calculated by the following established equation, which covers conditions from inhibition to induction [10,11]:…”