Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age

Abstract

Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

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Figures

FIG 1

Inclusion and exclusion criteria.

FIG 2

Trial flow chart.

FIG 3

Ciprofloxacin concentrations versus time. The solid line represents the population prediction of a typical patient.

FIG 4

Ciprofloxacin CL versus PMA.

FIG 5

Model evaluation for ciprofloxacin. (A) Population predicted (PRED) versus observed concentrations (DV); (B) individual predicted (IPRED) versus DV; (C) conditional weighted residuals (CWRES) versus time; (D) CWRES) versus PRED; (E) QQ-plot of the distribution of the normalized prediction distribution errors (NPDE) versus the theoretical N(0,1) distribution; (F) histogram of the distribution of the NPDE, with the density of the standard Gaussian distribution overlaid; (G) prediction-corrected visual predictive check. The circles represent the prediction-corrected observed concentrations. The solid line represent the median prediction-corrected observed concentrations and semitransparent gray field represents simulation-based 95% confidence intervals for the median. The observed 5th and 95th percentiles are indicated by dashed lines, and the 95% intervals for the model-predicted percentiles are indicated as corresponding semitransparent gray fields.

FIG 6

Ciprofloxacin CSF/serum concentration ratio versus time.

FIG 7

Target attainment rates and probability of overdose. The target attainment rates for the 100 simulated trials for MIC value of 0.5 mg/liter is presented as a function of the dose and age group. The AUC/MIC target is 125. Overdose is defined as an AUC over the maximum reported value of 291 mg·h/liter.

FIG 8

Model-based predicted impact of renal maturation on the clearance of ciprofloxacin in neonates. The influence of both gestational age (GA; representing antenatal maturation) and postnatal age (PNA; representing postnatal maturation) on renal maturation is depicted graphically.