A. van Rongen (1), F. van Oosterhout (2), M.J. Brill (1,3), J.H. Meijer (2), J. Burggraaf (3,4), C.A.J. Knibbe (1,3)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands, (3) Division of Pharmacology, Leiden/ Amsterdam Academic Center for Drug Research, Leiden University, Leiden, The Netherlands, (4) Centre for Human Drug Research, Leiden, The Netherlands
Objectives: Chronopharmacology studies have revealed circadian variability in pharmacokinetics and pharmacodynamics of different drugs. Time-dependent changes may occur for absorption, distribution, metabolism and/or excretion processes. The aim of this study is to evaluate the influence of circadian rhythm on the pharmacokinetic parameters of midazolam after oral and intravenous administration in a semi-simultaneous way.
Methods: The study was an open-label, 6 way crossover study in 12 healthy volunteers, in which at each of the 3 study visits the subjects received oral (2 mg) and iv (1 mg) midazolam (separated by 150 min) twice a day at a 12 hour interval. The clock times of midazolam dosage differed for each study occasion with a 4 hour interval and as a result data were collected at 6 time points to construct a 24 hour profile of midazolam pharmacokinetic parameters. Twenty samples were collected per patient per 12 hour interval. Population PK modelling and covariate modelling was performed using NONMEM VI.
Results: A two compartment pharmacokinetic model with an oral absorption transit compartment with ktr equal to ka best described the data with values of 0.38 L/min (CV of 7.5%), 21.8 L (4.3%), 0.35 (7.3%) and 0.06 min-1 (5.1%) for clearance, volume of distribution of the central compartment, oral bioavailability and ka, respectively. For oral bioavailability, a circadian night dip was identified which was parameterized as half a cycle of a sinus function. The amplitude representing the magnitude of the circadian variability was 0.08 (34.9%). Circadian rhythm was not found to influence any of the other pharmacokinetic parameters (p>0.05).
Conclusions: In this chronopharmacology study in 12 healthy volunteers, an influence of circadian rhythm was identified for oral bioavailability of midazolam representing a maximum reduction of 23% at night. Further research using physiologically-based modelling should elucidate which subprocess contributes to this circadian variability in bioavailability.
Reference: PAGE 22 () Abstr 2877 [www.page-meeting.org/?abstract=2877]
Poster: Other Modelling Applications