title: The influence of dosage time of midazolam on its pharmacokinetics and effects in humans.
abstract: The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.
authors.affiliation: Department of Medicine, University of Amsterdam, Academic Medical Center, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Koopmans
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: G P
authors.initials: GP
authors.lastname: Horsten
authors.forename: C J
authors.initials: CJ
authors.lastname: van Boxtel
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002849:Chromatography, Gas; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D004569:Electroencephalography; D005074:Evoked Potentials, Visual / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011869:Radioligand Assay
chemical_list: D008874:Midazolam