Population pharmacokinetic analysis for dose regimen optimization of vancomycin in Southern Chinese children

Abstract

Changes in physiological factors may result in large pharmacokinetic variability of vancomycin in pediatric patients, thereby leading to either supratherapeutic or subtherapeutic exposure and potentially affecting clinical outcomes. This study set out to characterize the disposition of vancomycin, quantify the exposure target and establish an optimal dosage regimen among the Southern Chinese pediatric population. Routine therapeutic drug monitoring data of 453 patients were available. We performed a retrospective population pharmacokinetic analysis of hospitalized children prescribed intravenous vancomycin using NONMEM® software. A one-compartment PPK model of vancomycin with body weight and renal functions as covariates based on a cutoff of 2 years old children was proposed in this study. Both internal and external validation showing acceptable and robust predictive performance of the model to estimate PK parameters. The value of area under the curve over 24 h to minimum inhibitory concentration ratio (AUC_0-24/MIC) ≥ 260 was a significant predictor for therapeutic efficacy. Monte Carlo simulations served as a model-informed precision dosing approach and suggested that different optimal dose regimens in various scenarios should be considered rather than flat dosing. The evaluation of vancomycin exposure-efficacy relationship indicated that lower target level of AUC_0-24/MIC may be needed to achieve clinical effectiveness in children, which was used to derive the recommended dosing regimen. Further prospective studies will be needed to corroborate and elucidate these results.

FIGURE 1

Study flow diagram. The overview of the study population enrollment process and study protocol.

FIGURE 2

Diagnostic goodness‐of‐fit (GOF) plots of the base model (1) and final model (2). (a) Observed concentration (DV) versus individual predicted concentration (IPRED); (b) DV versus population predicted concentration (PRED); (c) conditional weighted residuals (CWRES) versus PRED; and (d) CWRES versus time. The black solid lines are the reference lines, and red solid lines represent linear fit lines.

FIGURE 3

Simulated probability of target attainment (AUC ≥260) of vancomycin at each CLcr level for different dosage in patients with various body weights.