C. Barin-Le Guellec,1 W. Zhao,2 B. Kassai,3 M. A. Turner,4 E. Jacqz-Aigrain,2 on behalf of the TINN consortium; 1Pharmacogenetics Unit, Department of Biochemistry, Tours, France, 2Department of Paediatric Pharmacology and Pharmacogenetics, Paris, France, 3EPICIME-CIC 1407, Lyon, France, 4Neonatal unit, Liverpool Women's Hospital, Liverpool, United Kingdom

BACKGROUND: Because of insufficient pharmacokinetic and pharmacokinetic-pharmacodynamic evaluation, ciprofloxacin is used off-label in neonates with suspected or proven gram negative infection. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin and to define the appropriate dosing regimen in neonates and young infants < 3 months of age.
METHODS: Blood samples were collected from neonates treated with ciprofloxacin according to one of the two predefined 3-time point’s schedules and concentrations were measured by HPLC-MS. Population pharmacokinetic analysis was performed using NONMEM software.
RESULTS: The data from 60 newborn infants (postmenstrual age range: 24.9-47.9 weeks) were available for population pharmacokinetic analysis. Ciprofloxacin concentrations (n=430) ranged from 450 to 15976 ng/ml. A two-compartment model with first-order elimination best fitted the data. Covariate analysis revealed that gestational age, postnatal age, current weight, serum creatinine concentration and use of inotropic drugs had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with PMA<34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with PMA≥34 weeks and young infants receiving 12.5mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/L. The associated risks of overexposure for the proposed dosing regimen were less than 8%.
CONCLUSION: The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants < 3 months and a dosing regimen was established based on simulation.