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

Abstract

Objective: Identify population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH).

Design: 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.

Setting: A 189-bed children's tertiary care teaching hospital.

Results: Twelve patients, 5 (42%) females and 7 (58%) males, met inclusion criteria with a median gestation age of 39.9 weeks (interquartile range [IQR] 38.5-40.2 wks) 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 ± 0.7 ml/minute/kg, and the volume of the central compartment was 0.44 ± 0.06 L/kg. The R² , bias, and precision for the observed versus population predicted model were 0.917, 1.15, and 10.9 μg/ml; the R² , bias, and precision for the observed versus individual predicted model were 0.982, -0.132, and 0.932 μg/ml, respectively. The calculated mean population estimate for the total Vd was 0.96 ± 0.4 L/kg. The dosing regimen that most consistently produced a maximum concentration (C_max ) in the range of 10-12 mg/L with a minimum concentration (C_min ) level less than 2 mg/L was 5 mg/kg/dose given every 36 hours.

Conclusion: 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 5 mg/kg/dose every 36 hours results in a gentamicin C_max within the range of 10-12 mg/L with a C_min lower than 2 mg/L, which is appropriate for treating susceptible gram-negative organisms with minimum inhibitory concentrations of 1 mg/L or lower.

Keywords: antibiotic dosing; gentamicin; hypothermia; neonatal; pharmacodynamics; pharmacokinetics.