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Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

Jacqz-Aigrain E 1 , Leroux S 1 , Thomson AH 2 , Allegaert K 3 , Capparelli EV 4 , Biran V 5 Show all authors , Simon N 6 , Meibohm B 7 , Lo YL 8 , Marques R 9 , Peris JE 10 , Lutsar I 11 , Saito J 12 , Nakamura H 13 , van den Anker JN 14 , Sharland M 15 , Zhao W 1

Affiliations 

  • 1 Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France
  • 2 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
  • 3 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  • 4 Pediatric Pharmacology and Drug Discovery, University of California, San Diego, CA, USA
  • 5 Neonatal Intensive Care Unit, Hôpital Robert Debré, Paris, France
  • 6 Department of Pharmacology, Hôpital de la Timone, APHM, Université de la Méditerranée, Marseille, France
  • 7 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
  • 8 Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 9 Department of Pharmacy Services, La Fe Hospital, Valencia, Spain
  • 10 Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain
  • 11 Institute of Medical Microbiology, University of Tartu, Tartu, Estonia
  • 12 Department of Pharmacy, National Children's Hospital National Center for Child Health and Development, Tokyo, Japan
  • 13 Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
  • 14 Pharmacy Department, Glasgow Royal Infirmary, Glasgow, UK
  • 15 Paediatric Infectious Disease Unit, St George's Hospital, London, UK
J Antimicrob Chemother, 2019 08 01;74(8):2128-2138.
PMID: 31049551 DOI: 10.1093/jac/dkz158

Abstract

OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.

METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.

RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.

CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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