Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia

Author:

van der Veer Marlotte A. A.1ORCID,de Haan Timo R.2,Franken Linda G. W.1ORCID,van Hest Reinier M.1,Groenendaal Floris34,Dijk Peter H.5,de Boode Willem P.6,Simons Sinno7,Dijkman Koen P.8,van Straaten Henrica L. M.9,Rijken Monique10,Cools Filip11,Nuytemans Debbie H. G. M.2,van Kaam Anton H.2,Bijleveld Yuma A.1,Mathôt Ron A. A.1,

Affiliation:

1. Department of Pharmacy & Clinical Pharmacology Amsterdam University Medical Center Amsterdam The Netherlands

2. Department of Neonatology, Emma Children's Hospital Amsterdam University Medical Center Amsterdam The Netherlands

3. Department of Neonatology Wilhelmina Children's Hospital Utrecht The Netherlands

4. UMC Utrecht Brain Center University Medical Center Utrecht and Utrecht University Utrecht The Netherlands

5. University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatrics, Division of Neonatology University of Groningen Groningen The Netherlands

6. Department of Neonatology, Radboud University Medical Center, Radboud Institute for Health Sciences Amalia Children's Hospital Nijmegen The Netherlands

7. Department of Neonatal and Pediatric Intensive Care, Division of Neonatology Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands

8. Department of Neonatology Máxima Medical Center Veldhoven Veldhoven The Netherlands

9. Department of Neonatology Isala Clinics Zwolle The Netherlands

10. Department of Neonatology, Willem‐Alexander Children's Hospital Leiden University Medical Center Leiden The Netherlands

11. Department of Neonatology Vrije Universiteit Brussel Brussels Belgium

Abstract

AimsLittle is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment.MethodsNeonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed‐effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400–600 mg*h/L was used as target range.ResultsSixteen patients received vancomycin (median gestational age: 41 [range: 38–42] weeks, postnatal age: 4.4 [2.5–5.5] days, birth weight: 3.5 [2.3–4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1‐compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20–0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment.ConclusionResults of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model‐informed precision dosing.

Funder

ZonMw

Publisher

Wiley

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