Identifying 24 h variation in the pharmacokinetics of levofloxacin: a population pharmacokinetic approach

Laura Kervezee, Jasper Stevens, Willem Birkhoff, Ingrid M C Kamerling, Theo de Boer, Melloney Dröge, Johanna H Meijer, Jacobus Burggraaf

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AIM: 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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)256-268
Number of pages13
JournalBritish Journal of Clinical Pharmacology
Issue number2
Publication statusPublished - Feb-2016
Externally publishedYes


  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Bacterial Agents
  • Circadian Rhythm
  • Computer Simulation
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Glomerular Filtration Rate
  • Humans
  • Levofloxacin
  • Male
  • Middle Aged
  • Models, Biological
  • Thyrotropin
  • Young Adult
  • Journal Article
  • Randomized Controlled Trial

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