Variability of ciprofloxacin pharmacokinetics in children: Impact on dose range in sickle cell patients

Abstract

Objectives To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 €.,mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n € = € 20, 33%), haemopathy (n € = € 15, 25%), cystic fibrosis (CF; n € = € 3, 5%) and other diseases (n € € = € € 22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean € ± € € SD) was 0.81 € ± € 0.30 € L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.