Determination of appropriate weight-based cutoffs for empiric cefazolin dosing using data from a phase 1 pharmacokinetics and safety study of cefazolin administered for surgical prophylaxis in pediatric patients aged 10 to 12 years

Abstract

Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.).

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Figures

FIG 1

Scatterplot of cefazolin concentrations versus time since the start of infusion, colored by population and dose.

FIG 2

Scatterplots of observed cefazolin concentrations versus time since the start of infusion in pediatric patients overlaid upon the predicted distribution from the allometric-scaling-based model. Note that the solid circles represent the observed cefazolin concentrations and the broken line is the median cefazolin concentration at each nominal PK sampling time. The solid line is the median predicted concentration from the allometric population PK model; the gray band shows the 90% CI of the predicted concentrations.

FIG 3

Prediction-corrected visual predictive check with data from normal, healthy adults (top) and pediatric surgical patients (bottom). Note that the solid circles represent the observed cefazolin concentrations and the white dotted line is the median cefazolin concentration at each nominal PK sampling time; the black lines represent the 90% CI of the observed concentrations. The solid white line is the median predicted concentration for the respective population based on the revised population PK model; the gray band shows the 90% CI of the predicted concentrations.

FIG 4

Box-and-whisker plots of simulated AUC0–∞s of adolescents by age, stratified by weight cutoff. Note that the dashed horizontal line is the geometric mean of adults; the band represents 80 to 125% of the geometric mean. The line in the middle of the boxplot is the median, and the upper and lower limits of the box represent the 75th and 25th percentiles, respectively. The whiskers represent the upper and lower hinges, and the circles represent values outside the upper hinges.

FIG 5

Box-and-whisker plots of simulated AUC0–∞s of children by age, stratified by weight cutoff. Note that the dashed horizontal line is the geometric mean of adults; the band represents 80 to 125% of the geometric mean. The line in the middle of boxplot is the median, and the upper and lower limits of the box represent the 75th and 25th percentiles, respectively. The whiskers represent the upper and lower hinges, and the circles represent values outside the upper hinges.