Evaluation of Circadian Rhythms in Hepatic CYP3A4 Activity Using Population Pharmacokinetics of Midazolam
D. Tomalik-Scharte, D. Kunz, D. Rokitta, P. Di Gion, C. Queckenberg, U. Fuhr
Department of Pharmacology, Clinical Pharmacology, University of Cologne, K÷ln, Germany
Objectives: Chronopharmacology deals with the impact of circadian rhythms on the pharmacokinetics and pharmacodynamics of different drugs. Diurnal changes in the activity of drug metabolising enzymes may be an important factor affecting the variability in drug disposition. The aim of this study was to evaluate the role of circadian rhythms in the activity of hepatic CYP3A4, metabolizing nearly 50% of currently prescribed drugs.
Methods: Sixteen healthy volunteers, males and females, were given a continuous intravenous infusion with low-dosed midazolam (M), a well established model substrate of CYP3A4 activity. Blood samples for measurement of M and its main metabolite 1-OH-M were drawn hourly for 24 hours following the achievement of a steady-state. Population pharmacokinetic analysis was performed using NONMEM. Plasma concentrations of M and 1-OH-M were fitted by a two-compartment base model (parent and metabolite) using first order conditional estimation. To evaluate circadian changes in CYP3A4 activity, the variability in the steady-state clearance of M was modelled by a cosine function with a 24-h period.
Results: The circadian model yielded an improvement of 92 points in the NONMEM objective function over the base model. The average clearance of M (%CV) was 22.4L/h (7%). The mean amplitude of the cosine function, describing the magnitude of the circadian variability in CYP3A4 activity, was 2.97L/h and the peak time, corresponding to the maximal clearance value, was at about 12:30.
Conclusions: The results of this pilot study provide evidence for a circadian variability in CYP3A4 activity, however, its effect seems to be moderate. Further population studies are needed to explore the clinical relevance of circadian rhythms in CYP3A4 activity for the treatment with drugs metabolized via this enzyme.