Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam

Abstract

Diurnal changes in the activity of drug metabolizing enzymes may contribute to the variability in drug disposition and drug effects. The aim of this study was to quantify the circadian rhythmicity exhibited by hepatic CYP3A. A 10 μg/kg intravenous bolus dose, followed by a 30-hour 4 μg/kg/h intravenous infusion of midazolam, used as a probe substrate for hepatic CYP3A activity, was administered to 16 healthy volunteers (8 males and 8 females). Blood samples were drawn hourly for 24 hours after achieving steady state, and plasma concentrations of midazolam and its main metabolite 1-OH midazolam were determined. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. One-compartment pharmacokinetic models best described midazolam and 1-OH midazolam pharmacokinetic disposition. An unequivocal but minor diurnal pattern was identified in the midazolam plasma concentration profiles, which was described using a cosine function with a 24-hours period. The fluctuation in the relative CYP3A activity ranged between 10% above average around 15:00, and 10% below average around 03:00. None of the covariates tested had a significant impact on the parameters estimated. Although a diurnal pattern in hepatic CYP3A activity was identified, its magnitude suggests that it is small and without clinical significance for drug therapy.

Effect of diurnal variation,CYP2B6genotype and age on the pharmacokinetics of nevirapine in African children

“…28,60,61 Our study replicated those findings and detected significantly higher nevirapine clearance during the day, with a maximum at midday. The estimated amplitude of the diurnal variation is somewhat larger than previous reports in CYP3A4 probes.…”

“…The estimated amplitude of the diurnal variation is somewhat larger than previous reports in CYP3A4 probes. 28,60 This could be due to the considerable contribution of CYP2B6 enzymes to nevirapine clearance. Although little is known about the chrono-pharmacokinetics of this pathway, our hypothesis is supported by the fact that CAR, which regulates expression of CYP2B6 , 21 exhibits a circadian rhythm linked to a 1.7-fold magnitude induction of CYP2B mRNA.…”

“…26,27 Additionally, CYP3A activity exhibits diurnal variation, with nevirapine clearance rates increasing during the day and reducing at night. 28,29 Differences between morning (AM) and evening (PM) nevirapine trough concentrations ( C min ) have been previously reported 30 and may relate to diurnal variation in the CYP3A -mediated effects on pharmacokinetics.…”

Population Pharmacokinetic Model Characterizing 24‐Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers

“…Several chronopharmacokinetic studies on midazolam have been published 15–19. In most of these studies, however, midazolam was administered either orally18 or as an intravenous (i.v.)…”

“…In most of these studies, however, midazolam was administered either orally18 or as an intravenous (i.v.) infusion,15,17,19 and therefore not all PK parameters (absorption rate constant, bioavailability, and clearance) could be assessed separately. To distinguish between bioavailability, systemic clearance, and volume of distribution, oral and i.v.…”