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 (Cmax) in the range of 10–12 mg/L with a minimum concentration (Cmin) 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 Cmax within the range of 10–12 mg/L with a Cmin lower than 2 mg/L, which is appropriate for treating susceptible gram‐negative organisms with minimum inhibitory concentrations of 1 mg/L or lower.

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept

“…Still, many attempts have been done to provide dosing recommendations using popPK. We found 18 popPK studies providing dosing recommendations for term neonates and/or infants (17,18,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70). Only 4 of these studied the same population and the same therapeutic window as we did (55,58,61,69) C max and C trough levels and their 5th and 95th percentiles in infants 4-6 weeks of age upon a 7.5 mg/kg dose.…”

Pharmacometric approach to assist dosage regimen design in neonates undergoing therapeutic hypothermia

“…The majority of the reports on gentamicin showed a reduction in CL during TH, while there were reports of an increase and no change in CL as well. 14,[23][24][25][26][27][28] A recent metaanalysis reported that CL of gentamicin was reduced during TH. 29 In this study, they have summarized the results from the published studies and reported reduced CL of gentamicin during TH.…”

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia

“…11,12 Among the 3 published gentamicin PK models in this specific patient population, our study presented the first PK model that incorporated prospectively collected data sampled at multiple time points throughout all phases of controlled TH. 8,13,14 This model was validated using advanced internal methods [bootstrap and normalized prediction distribution error (NPDE) analysis], but no external validation had been conducted. 8 In this study, we assessed the predictive performance and generalizability of our original gentamicin PK model using an independent data set of (near) term neonates with perinatal asphyxia undergoing controlled TH.…”