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

YA Bijleveld, Timo R de Haan, Johanna van der Lee, F Groenendaal, Peter H Dijk, A van Heijst, RC de Jonge, KP Dijkman, Henrica LM van Straaten, M Rijken, Inge A Zonnenberg, Filip Cools, Alexandra Zecic, Debbie HGM Nuytemans, Anton Van Kaam, Ron AA Mathôt, PharmaCool study group

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7 Citations (Scopus)


The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. 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 that of 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 multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/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 every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 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
Article numbere02311-17
Number of pages13
JournalAntimicrobial Agents and Chemotherapy
Issue number4
Publication statusPublished - Apr 2018

Bibliographical note

Copyright © 2018 American Society for Microbiology.


  • Benzylpenicillin
  • Moderate hypothermia
  • Neonate
  • Perinatal asphyxia
  • Population pharmacokinetics


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