Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients

Abstract

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a twocompartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V 2 ), volume of the peripheral compartment (V 3 ), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL ‫؍‬ 8.8 ؉ 0.396 ⅐ WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V 2 and V 3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V 2 and V 3 , respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation

“…This range is lower than the values averaging ∼8.4 mg/L reported by Schaefer et al . 18 following intravenous doses of 10 mg/kg to paediatric patients with cystic fibrosis, but is consistent, when corrected for dose, with their range of ∼2.5–5 mg/L (mean 3.5 mg/L) achieved with an oral dose of 15 mg/kg. In contrast, despite using a higher dose of 15 mg/kg, Peltola et al 19 observed similar values of C max (0.5–5.3 mg/L) when they administered ground tablets in water and mean C max values of ∼2–2.7 mg/L following an oral suspension of 10 mg/kg.…”

“…Studies following the intravenous administration of ciprofloxacin have identified a biexponential decline with a short distribution half-life of ∼10–30 min, 16–18,35,36 but the sparse sampling schedule in the present study precluded the identification of a distribution phase. The population model indicated a rapid absorption of ciprofloxacin with an estimated half-life of 14 min after a lag of ∼45 min.…”

“…14 In its many years of clinical use, ciprofloxacin has been found effective, even with oral administration, owing to its bioavailability of ∼70%. 15 However, few studies have evaluated the population pharmacokinetics of ciprofloxacin in children, 16–18 and no studies have been conducted in severe malnutrition.…”

Safety Concerns Surrounding Quinolone Use in Children

“…In particular, it has been suggested that daily doses must be at least 30 mg/(kg·day) intravenously or 40 mg/(kg·day) orally. 18,19 …”

Transcutaneous sampling of ciprofloxacin and 8-methoxypsoralen by electroporation (ETS technique)

“…The spiked plasma samples were thoroughly mixed by vortexing and allowed to equilibrate for 12 h at 4°C. After equilibration, protein free plasma was obtained by carrying out ultra filtration (Millipore Centrifree ® filtration units) by centrifugation of 0.5 ml of plasma at 2000g for 20 min (Schaefer et al, 1996, Murthy et al, 2005). The amount of unbound drug present in the filtrate was measured by HPLC after suitable dilution with PBS.…”