title: Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers.
abstract: Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital Nieuwegein, The Netherlands ; Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Rongen
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University Leiden, The Netherlands ; Department of Molecular Cell Biology, Leiden University Medical Center Leiden, The Netherlands ; Centre for Human Drug Research Leiden, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Kervezee
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital Nieuwegein, The Netherlands ; Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University Leiden, The Netherlands.
authors.forename: Mje
authors.initials: M
authors.lastname: Brill
authors.affiliation: Centre for Human Drug Research Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Meir
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: den Hartigh
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center Leiden, The Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center Leiden, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Meijer
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University Leiden, The Netherlands ; Centre for Human Drug Research Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center Leiden, The Netherlands ; Centre for Human Drug Research Leiden, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: van Oosterhout