Evaluation of a System-specific Function to Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia

Yuma A. Bijleveld, Timo R. de Haan, Johanna H. van der Lee, Floris Groenendaal, Peter H. Dijk, Arno van Heijst, Rogier C. J. de Jonge, Koen P. Dijkman, Henrica L. M. van Straaten, Monique Rijken, Inge A. Zonnenberg, Filip Cools, Alexandra Zecic, Debbie H. G. M. Nuytemans, Anton H. van Kaam, Ron A. A. Mathôt

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The pharmacokinetic (PK) properties of i.v. benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as to date these are unknown. To do so, a system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature induced changes in amoxicillin clearance (CL) in the same patient study population, was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW) based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to a reference-model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose.The system-specific model performed as well as the reference-model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model) and multi-organ-failure (reference-model). For a typical patient GA 40 weeks, BW3000 g, 2 days PNA (TEMP 33.5°C), and normal UO (2 ml/kg/h)) benzylpenicillin CL was 0.48 L/h (inter-individual variability (IIV) 49%) and volume of distribution of the central compartment was 0.62 L/kg (IIV of 53%) in the system-specific model.Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day q8h, 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GA36-37 weeks, 38-41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development
Original languageEnglish
Pages (from-to)e02311-17
JournalAntimicrobial agents and chemotherapy
Issue number4
Publication statusPublished - Apr 2018


  • benzylpenicillin
  • moderate hypothermia
  • neonate
  • perinatal asphyxia
  • population pharmacokinetics

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