Population Pharmacokinetics of Ciprofloxacin in Pediatric Patients
The objective of this study was to characterize ciprofloxacin population pharmacokinetics in pediatric patients. A total of 150 pediatric patients (including 28 patients with cystic fibrosis [CF], ages 0.27-16.9 years) received ciprofloxacin by the oral and/or intravenous routes. Population pharmacokinetic analyses were performed with NONMEM software. Exponential error models were used to describe the interindividual variance in pharmacokinetic parameters, and the residual error model included both proportional and additive components. Based on principles of allometry, the patient's body weight was used as a covariate, along with appropriate allometric exponents, in the construction of the base model. Model building was accomplished by a stepwise forward inclusion procedure, and the final model was evaluated by multiple techniques, including bootstrap, leverage analysis, and cross-validation. With body weight included in the model (two compartments with first-order absorption), ciprofloxacin clearance was influenced by age, and the absorption rate constant was altered in CF patients. The final model is summarized as follows: CL (L/h) = 30.3 × (WT/70)0.75 × (1 + 0.045 [AGE - 2.5]), VC (L) = 56.7 × (WT/70)1.0,VP (L) = 89.8 × (WT/70)1.0, Q (L/h) = 37.5 × (WT/70)0.75, Ka (1/h) = 1.27 × (1 + [-0.611 × CF]), absorption lag time = 0.35 hours, and bioavailability fraction = 61.1%, where WT and AGE are the patient's body weight (kg) and age (years), respectively, and the variable CF equals 1 for CF patients and 0 for non-CF patients. The interpatient variability in pharmacokinetic parameters (percentage coefficient of variation [%CV]) ranged from 22.5% to 49.8%. The residual variabilities (%CV) for the oral and intravenous data were 40% and 27%, respectively. The shared additive residual variance component was small (SD = 0.04 mg/L). Model evaluation by the different methods indicated that the final model was robust and parameter estimates were precise. A small difference (< 6%) was noted when the patient's age was not used in dose calculation. Therefore, in routine clinical use, for pediatric patients older than 3 months, ciprofloxacin dose may be calculated solely based on body weight.