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

Marlotte A A van der Veer; Timo R de Haan; Linda G W Franken; Reinier M van Hest; Floris Groenendaal; 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; PharmaCool Study Group

doi:10.1111/bcp.16026

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

Br J Clin Pharmacol. 2024 Mar 7. doi: 10.1111/bcp.16026. Online ahead of print.

Authors

Marlotte A A van der Veer¹, Timo R de Haan², Linda G W Franken¹, Reinier M van Hest¹, Floris Groenendaal^{3

4}, Peter H Dijk⁵, Willem P de Boode⁶, Sinno Simons⁷, Koen P Dijkman⁸, Henrica L M van Straaten⁹, Monique Rijken¹⁰, Filip Cools¹¹, Debbie H G M Nuytemans², Anton H van Kaam², Yuma A Bijleveld¹, Ron A A Mathôt¹; PharmaCool Study Group

Affiliations

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.

PMID: 38450797
DOI: 10.1111/bcp.16026

Abstract

Aims: Little 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.

Methods: Neonates 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.

Results: Sixteen 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.

Conclusion: Results 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.

Keywords: antimicrobial therapy; neonates; perinatal asphyxia; pharmacokinetics; therapeutic hypothermia; vancomycin.

Abstract

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