Pharmacokinetics and Optimal Dose Selection of Cefazolin for Surgical Prophylaxis of Pediatric Patients

Abstract

Cefazolin is an antibiotic frequently used for perioperative prophylaxis. Data from healthy adults and pediatric surgery patients were pooled to refine a previously developed population pharmacokinetic (PK) model and to determine the optimal body weight cutoff for selecting fixed doses of either 1 or 2 g cefazolin to produce exposures in pediatric surgery patients similar to a single 2-g dose in adults. Regardless of dose used, cefazolin was well tolerated in pediatric patients. A total of 1102 plasma samples from 62 patients from 3 studies were available to assess the previous model. The pooled data set allowed for simplification of the model such that allometrically scaled clearance and volume parameters were found to provide a robust fit while removing unnecessary covariate relationships. Monte Carlo simulations using the final cefazolin population PK model suggested an optimal weight cutoff of 50 kg, in contrast to the previously suggested 60 kg for a single 2-g dose. Patients at or above this 50-kg cutoff would receive a 2-g dose of cefazolin, and those below 50 kg but ≥25 kg would receive a 1-g dose of cefazolin.

Keywords: cefazolin; model-based simulations; pharmacokinetics; surgical prophylaxis.

Conflict of interest statement

Diana Valencia Martinez, Diane Licursi, Angela Karpf, and Wes Cetnarowski are employees of B. Braun Medical Inc. Michael Schmitz was a principal investigator for Studies HC‐G‐H‐0906 and HC‐G‐H‐1601, and his institution was paid by B. Braun for that participation. At the time this study was conducted, Christopher Rubino and Nikolas Onufrak were employees of Institute for Clinical Pharmacodynamics, Inc. which received consulting fees from B. Braun Medical Inc.

© 2020 B. Braun Medical Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Cefazolin plasma concentration versus time through the first 8 hours, stratified by study and dose (A) or by population and study (B). h, hour; L, liter, mg, milligram. Solid lines represent loess smoothers through the data.

Figure 2

Goodness‐of‐fit plots for the final cefazolin population PK model. Two conditional weighted residual (CWRES) values eclipsed the threshold value of ±4 but were ultimately retained secondary to their inability to influence either population‐ or individual‐level fitting. Dashed lines represent reference lines (line of identity, top; zero‐residual line, bottom); solid lines represent lines of best fit (top) or loess smoothers through the data (bottom). h, hour; mg, milligram.

Figure 3

Prediction‐corrected visual predictive checks using the final cefazolin population PK model, stratified by patient population. PFLAG represents flag variable for denoting whether the population is healthy adults (PFLAG = 0) or pediatric patients (PFLAG = 1). Black lines represent 50th (solid) and 5th/95th percentiles (dashed) of the observed data; dark blue shaded region represents the 90% prediction interval around the 50th percentile of predictions; light blue‐shaded regions represent 90% prediction intervals around the 5th (lower) and 95th (upper) percentiles of predictions. h, hour; L, liter; mg, milligram.

Figure 4

Box‐and‐whisker plots of simulated AUC0‐∞ by age in virtual pediatric populations aged 10 to 17 years, stratified by minimal weight cutoff for the administration of a 2‐g cefazolin dose. Dashed horizontal line is geometric mean for adults; band represents 80% to 125% of geometric mean. Line in middle of the box is the median; upper and lower limits of the box represent the 75th and 25th percentiles, respectively. AUC0‐∞, estimated area under the curve from time zero to infinity; h, hour; kg, kilogram; L, liter; mg, milligram; y, years.

Figure 5

Box‐and‐whisker plots of simulated AUC0‐∞ in a singular virtual pediatric population aged 10 to 17 years, stratified by minimal weight cutoff for the administration of a 2‐g cefazolin dose. Dashed horizontal line is geometric mean for adults; dotted top and bottom lines represents 80% to 125% of geometric mean. Line in middle of the box is the median, upper and lower limits of the box represent the 75th and 25th percentiles, respectively. AUC0‐∞, estimated area under the curve from time zero to infinity; h, hour; kg, kilogram; L, liter; mg, milligram.