Rapid Implementation of Model-Based Dosing Recommendations During the Coronavirus Disease 2019 Pandemic | JAMA Pediatrics | JAMA Network
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Comment & Response
January 4, 2021

Rapid Implementation of Model-Based Dosing Recommendations During the Coronavirus Disease 2019 Pandemic

Author Affiliations
  • 1Intensive Care and Department of Paediatric Surgery, Erasmus MC–Sophia Children’s Hospital, Rotterdam, the Netherlands
  • 2Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
  • 3Department of Paediatrics, Erasmus MC, Sophia Children's Hospital, Rotterdam, the Netherlands
JAMA Pediatr. 2021;175(4):432-433. doi:10.1001/jamapediatrics.2020.5395

To the Editor With great interest, we read the article by Maharaj et al1 and the accompanying Editorial by Watt.2 We can only applaud the authors, the Pediatric Trial Network, and the journal for showing the pediatric community the added value of modeling and simulation in situations where pediatric data are scarce. We would like to take the opportunity to stress the importance of translating these model-based dosing guidelines to clinical care. Most pediatricians are not familiar with pharmacokinetic articles and may be hesitant to use simulated doses from scientific publications in real-life clinic.

Chloroquine, hydroxychloroquine, and remdesivir were recommended at the start of the pandemic by the Dutch Centre for Infectious Disease Control for both adults and children. Because specific dosing guidelines for children were missing, the Dutch Paediatric Formulary, the nationwide resource for pediatric drug doses, assessed the risk-benefit for pediatric use based on peer-reviewed pediatric malaria and Ebola virus studies, (limited) adult data from patients with coronavirus disease 2019, the adult coronavirus disease 2019 dosing advice, and expert opinion.3 Doses were next published on our website to ensure access to prescribing physicians.

In addition, supported by a recent Bill & Melinda Gates Foundation grant, we used physiologically based pharmacokinetic modeling for the recommendation of pediatric chloroquine doses,4 similar to the approach taken by Maharaj et al.1 As published pediatric pharmacokinetic data were available from studies in patients with malaria, we verified our model for children as young as 6 months old. Two weeks after the publication of the pragmatic best-evidence dose, we replaced the dosing advice with the model-based dose on both our own and on our international affiliates websites.5 Moreover, the European Network of Paediatric Research at the European Medicines Agency shared our dose advice with its members after acceptance of the peer-reviewed publication.

We will now use the above decision framework to evaluate the published doses by Maharaj et al1 and adjust our current doses of pragmatic best-evidence doses of hydroxychloroquine and remdesivir when needed. We hope others will take our example and thereby ensure physicians across the globe have access to pragmatic yet evidence-based dosing information to treat children with the highest chance of an effective and safe therapy. We are curious to learn from the authors how the Pediatric Trials Network supports implementation of dosing recommendations in real-life clinical care.

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Article Information

Corresponding Author: Saskia N. de Wildt, MD, PhD, Department of Pharmacology and Toxicology, Radboud University Medical Center, Geert Grooteplein 21 (route 117), 6525 EZ Nijmegen, the Netherlands; PO Box 9101, 6500 HB Nijmegen, the Netherlands (saskia.dewildt@radboudumc.nl).

Published Online: January 4, 2021. doi:10.1001/jamapediatrics.2020.5395

Conflict of Interest Disclosures: Dr de Wildt reports grants from Bill & Melinda Gates Foundation during the conduct of the study; grants from EU Horizon, IMI2, and Health Holland outside the submitted work; and serves as medical director of Dutch Knowledge Center for Children and as such is responsible for Dutch Paediatric Formulary and its international affiliates. Dr Van der Zanden reports grants from Dutch Ministry of Health during the conduct of the study; and is the managing director of the Dutch Paediatric Formulary.

Funding/Support: This Letter is based on research funded in part by the Bill & Melinda Gates Foundation (grant INV-001822).

Role of the Funder/Sponsor: The funder had no role in the preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation.

Maharaj  AR, Wu  H, Hornik  CP,  et al; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.  Simulated assessment of pharmacokinetically guided dosing for investigational treatments of pediatric patients with coronavirus disease 2019.   JAMA Pediatr. 2020;174(10):e202422. doi:10.1001/jamapediatrics.2020.2422PubMedGoogle Scholar
Watt  KM.  How to rapidly determine first-in-children dosing for COVID-19 therapeutics.   JAMA Pediatr. 2020;174(10):e202435. doi:10.1001/jamapediatrics.2020.2435PubMedGoogle Scholar
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Verscheijden  LFM, van der Zanden  TM, van Bussel  LPM,  et al.  Chloroquine dosing recommendations for pediatric COVID-19 supported by modeling and simulation.   Clin Pharmacol Ther. 2020;108(2):248-252. doi:10.1002/cpt.1864PubMedGoogle ScholarCrossref
Kinderformularium. Chloroquine. Accessed June 6, 2020. https://www.kinderformularium.nl/geneesmiddel/2664/chloroquine