title: Identifying 24 h variation in the pharmacokinetics of levofloxacin: a population pharmacokinetic approach.
abstract: OBJECTIVE
  The objective of this study was to investigate whether the pharmacokinetics of orally administered levofloxacin show 24 h variation. Levofloxacin was used as a model compound for solubility and permeability independent absorption and passive renal elimination.
  
  
  METHODS
  In this single centre, crossover, open label study, 12 healthy subjects received an oral dose of 1000 mg levofloxacin at six different time points equally divided over the 24 h period. Population pharmacokinetic modelling was used to identify potential 24 h variation in the pharmacokinetic parameters of this drug.
  
  
  RESULTS
  The pharmacokinetics of levofloxacin could be described by a one compartment model with first order clearance and a transit compartment to describe drug absorption. The fit of the model was significantly improved when the absorption rate constant was described as a cosine function with a fixed period of 24 h, a relative amplitude of 47% and a peak around 08.00 h in the morning. Despite this variation in absorption rate constant, simulations of a once daily dosing regimen showed that tmax , Cmax and the area under the curve at steady-state were not affected by the time of drug administration.
  
  
  CONCLUSIONS
  The finding that the absorption rate constant showed considerable 24 h variation may be relevant for drugs with similar physicochemical properties as levofloxacin that have a narrower therapeutic index. Levofloxacin, however, can be dosed without taking into account the time of day, at least in terms of its pharmacokinetics.
authors: Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden.|Centre for Human Drug Research, Leiden.
authors: Laura
authors: L
authors: Kervezee
authors: Centre for Human Drug Research, Leiden.
authors: Jasper
authors: J
authors: Stevens
authors: Centre for Human Drug Research, Leiden.
authors: Willem
authors: W
authors: Birkhoff
authors: Centre for Human Drug Research, Leiden.
authors: Ingrid M C
authors: IM
authors: Kamerling
authors: ABL Laboratories, Assen, the Netherlands.
authors: Theo
authors: T
authors: de Boer
authors: ABL Laboratories, Assen, the Netherlands.
authors: Melloney
authors: M
authors: Dröge
authors: Laboratory for Neurophysiology, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden.
authors: Johanna H
authors: JH
authors: Meijer
authors: Centre for Human Drug Research, Leiden.
authors: Jacobus
authors: J
authors: Burggraaf
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002940:Circadian Rhythm; D003198:Computer Simulation; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005919:Glomerular Filtration Rate; D006801:Humans; D064704:Levofloxacin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D013972:Thyrotropin / Q000097:blood; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D013972:Thyrotropin
keywords: chronopharmacokinetics; diurnal variation; fluoroquinolone; population pharmacokinetic modelling; time of administration