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

AimThe objective of this study was to investigate whether the pharmacokinetics of orally administered levofloxacin show 24h variation. Levofloxacin was used as a model compound for solubility and permeability independent absorption and passive renal elimination. MethodsIn this single centre, crossover, open label study, 12 healthy subjects received an oral dose of 1000mg levofloxacin at six different time points equally divided over the 24h period. Population pharmacokinetic modelling was used to identify potential 24h variation in the pharmacokinetic parameters of this drug. ResultsThe 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 24h, a relative amplitude of 47% and a peak around 08.00h in the morning. Despite this variation in absorption rate constant, simulations of a once daily dosing regimen showed that t(max), C-max and the area under the curve at steady-state were not affected by the time of drug administration. ConclusionThe finding that the absorption rate constant showed considerable 24h 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.