Population Pharmacokinetics and Dose Optimization of Vancomycin in Critically Ill Children.

Abstract

BACKGROUND AND OBJECTIVE\nCritically ill children may exhibit varied vancomycin pharmacokinetic parameters mainly due to altered protein binding, extracellular volume, and renal elimination. The objective of this study was to assess the pharmacokinetics of vancomycin in critically ill children and determine the optimum dose regimen.\n\n\nMETHODS\nThis was a cross-sectional study of critically ill children admitted to a pediatric intensive care unit. They received vancomycin dose of 15 mg/kg every 8\xa0h for mild infections or every 6\xa0h if infection was moderate or severe. A nonlinear mixed-effects modeling approach was applied in estimating pharmacokinetic parameters using Monolix 2019R2®. We performed Monte Carlo simulations to assess and optimize the dosing regimen using Simulx®. We used the ratio of the area under the concentration-time curve up to 24\xa0h to minimum inhibitory concentration (AUC0-24/MIC) ≥ 400 as the pharmacokinetic-pharmacodynamic target.\n\n\nRESULTS\nFifty-eight critically ill children with 145 concentrations were included in the present study. A one-compartment pharmacokinetic model with linear elimination described the concentration-time profile well. The estimated median (95% confidence intervals) volume of distribution (Vd) was 13.3 (10.8-16.5) l and clearance (CL) was 1.23 (1.03-1.45) l/h. Creatinine clearance significantly affected the CL of vancomycin. Monte Carlo simulations revealed that a dose of either 15 mg/kg 6 hourly or 20 mg/kg 8 hourly was likely to result into most critically ill children attaining the vancomycin lead pharmacokinetic-pharmacodynamic target.\n\n\nCONCLUSION\nWe established pharmacokinetic parameters of vancomycin for critically ill children. We also observed that the current dosing regimen practiced in the intensive care unit was inadequate for achieving the pharmacokinetic-pharmacodynamic target. We recommend vancomycin dose escalation in critically ill pediatric patients from 15 mg/kg 8 hourly (current dosing regimen) to either 6 hourly or 20 mg/kg 8 hourly with intense therapeutic drug monitoring for adverse effects.