Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

Abstract

This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24h/MIC ratio ≥ 125. A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. The recommended IV dose of 10mg/kg q8h, not exceeding 400mg q8h, would achieve AUC0-24h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600mg q8h in children > 40kg and to 15mg/kg q8h (max 400mg q8h, max 600mg q8h if augmented renal clearance, i.e., eGFR > 200mL/min/1.73 m2) in children < 40kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20mg/kg q12h (not exceeding 750mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.