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

Marlotte A.A. Van Der Veer*, Timo R. De Haan, Linda G.W. Franken, Floris Groenendaal, for the PharmaCool Study Group, Peter H. Dijk, Willem P. De Boode, Sinno Simons, Koen P. Dijkman, Henrica L.M. Van Straaten, Monique Rijken, Filip Cools, Debbie H.G.M. Nuytemans, Anton H. Van Kaam, Yuma A. Bijleveld, Ron A.A. Mathôt, Mieke J. Brouwer, Marcel P. Van Den Broek, Carin M.A. Rademaker, Djien LiemKaterina Steiner, Annelies A. Bos, S. M.Mulder De Tollenaer, L. J.M.Groot Jebbink-Akkerman, Michel Sonnaert, Fleur Anne Camfferman

*Corresponding author for this work

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Abstract

Background:Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH.Methods:The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed.Results:The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters.Conclusions:The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

Original languageEnglish
Pages (from-to)376-383
Number of pages8
JournalTherapeutic Drug Monitoring
Volume46
Issue number3
DOIs
Publication statusPublished - 1 Jun 2024

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