Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic-Ischemic Encephalopathy Receiving Controlled Hypothermia.

Abstract

Identify population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). Prospective open-label pharmacokinetic study. Gentamicin concentrations were modeled and dosing regimens simulated for a 5000-patient neonatal population with HIE receiving CH using PMetrics, a nonparametric, pharmacometric modeling, and simulation package for R. A 189-bed children's tertiary care teaching hospital. Twelve patients, 5 (42%) females and 7 (58%) males, met inclusion criteria with a median gestation age of 39.9weeks (interquartile range [IQR] 38.5-40.2wks) and a median birthweight (BW) of 3.3 kg (IQR 3.1-3.7 kg). Gentamicin concentrations were best described by a two-compartment model with first-order elimination with BW as a covariate on volume of distribution (Vd). The mean total body population clearance (CL) was 2.2±0.7ml/minute/kg, and the volume of the central compartment was 0.44±0.06L/kg. The R2 , bias, and precision for the observed versus population predicted model were 0.917, 1.15, and 10.9μg/ml; the R2 , bias, and precision for the observed versus individual predicted model were 0.982, -0.132, and 0.932μg/ml, respectively. The calculated mean population estimate for the total Vd was 0.96±0.4L/kg. The dosing regimen that most consistently produced a maximum concentration (Cmax ) in the range of 10-12mg/L with a minimum concentration (Cmin ) level less than 2mg/L was 5mg/kg/dose given every 36hours. These data suggest the population pharmacokinetics of gentamicin in neonates with HIE receiving CH have an increase in gentamicin CL and are different from previous reports in neonates with HIE not receiving CH and/or neonates without HIE. This analysis suggests a dosing regimen of 5mg/kg/dose every 36hours results in a gentamicin Cmax within the range of 10-12mg/L with a Cmin lower than 2mg/L, which is appropriate for treating susceptible gram-negative organisms with minimum inhibitory concentrations of 1mg/L or lower.