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What are appropriate dosing strategies for hydroxychloroquine and remdesivir in children with coronavirus disease 2019?
In this simulation-based dose-ranging study, pediatric dosing strategies were devised that provided similar exposures between children within different developmental stages and adults. However, the analysis raised concerns regarding hydroxychloroquine use for coronavirus disease 2019 treatment because unbound plasma concentrations were less than those postulated to mediate an antiviral effect.
To confirm the appropriateness of the proposed dosing schemes, prospective pharmacokinetic, safety, and efficacy studies in children are required.
Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required.
To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment.
Design, Setting, and Participants
Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population.
Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies.
Main Outcomes and Measures
The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration.
For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL).
Conclusions and Relevance
This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.
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Corresponding Author: Michael Cohen-Wolkowiez, MD, PhD, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705 (email@example.com).
Accepted for Publication: May 13, 2020.
Published Online: June 5, 2020. doi:10.1001/jamapediatrics.2020.2422
Author Contributions: Dr Cohen-Wolkowiez had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Maharaj, C. P. Hornik, Balevic, Smith, Benjamin, Cohen-Wolkowiez.
Acquisition, analysis, or interpretation of data: Maharaj, Wu, C. P. Hornik, Balevic, C. D. Hornik, Gonzalez, Zimmerman, Cohen-Wolkowiez.
Drafting of the manuscript: Maharaj, Wu, C. P. Hornik, C. D. Hornik.
Critical revision of the manuscript for important intellectual content: Maharaj, C. P. Hornik, Balevic, C. D. Hornik, Smith, Gonzalez, Zimmerman, Benjamin, Cohen-Wolkowiez.
Statistical analysis: Maharaj, Wu, C. P. Hornik, Balevic.
Obtained funding: Benjamin, Cohen-Wolkowiez.
Administrative, technical, or material support: C. D. Hornik, Cohen-Wolkowiez.
Supervision: C. P. Hornik, Benjamin, Cohen-Wolkowiez.
Conflict of Interest Disclosures: Dr C. P. Hornik reported personal fees from Anavex Pharmaceuticals and grants from Pfizer outside the submitted work. Dr Balevic reported grants, nonfinancial support, and other support from the US Food and Drug Administration, grants from the National Institutes of Health, Patient-Centered Outcomes Research Institute, Rheumatology Research Foundation, Thrasher Research Fund, and Childhood Arthritis and Research Alliance/Arthritis Foundation; and personal fees from UCB outside the submitted work. Dr Gonzalez reported a travel grant through the University of North Carolina at Chapel Hill to give a presentation at Boehringer Ingelheim outside the submitted work and support for research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Zimmerman reported grants from the National Institutes of Health during the conduct of the study. Dr Maharaj receives research support from the Thrasher Research Fund (www.thrasherresearch.org). Dr Smith receives funding from the National Institutes of Health. Dr Benjamin receives support from the National Institutes of Health, National Institute of Child Health and Human Development, the National Center for Advancing Translational Sciences, and Food and Drug Administration and personal fees from Astellas Pharma, Cidara Therapeutics, Allergan, and Lediant outside the submitted work. Dr Cohen-Wolkowiez receives support from the National Institutes of Health, National Institute of Child Health and Human Development, the National Center for Advancing Translational Sciences, and the US Food and Drug Administration; he also receives research support from industry for neonatal and pediatric drug development. No other disclosures were reported.
Funding/Support: This work was funded through support from the National Institutes of Health grant 1K24-AI143971 (Dr Cohen-Wolkowiez). This work was also funded under the National Institute of Child Health and Human Development contract (HHSN275201000003I) for the Pediatric Trials Network (Principal Investigator, Dr Benjamin).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee Members: Daniel K. Benjamin Jr, MD, PhD, MPH, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Christoph P. Hornik, MD, PhD, MPH, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Kanecia O. Zimmerman, MD, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Phyllis Kennel, MS, RD, LDN, PMP, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Rose Beci, BS, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; Chi Dang Hornik, PharmD, Duke University Medical Center, Durham, North Carolina; Gregory L. Kearns, BSc (Pharm), PharmD, PhD, TCU-UNTHSC School of Medicine, Fort Worth, Texas; Matthew Laughon, MD, MPH, University of North Carolina at Chapel Hill; Ian M. Paul, MD, MSc, Penn State College of Medicine, Hershey, Pennsylvania; Janice E. Sullivan, MD: University of Louisville, Louisville, Kentucky; Kelly Wade, MD, PhD, MSCE, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Paula Delmore, MSM, Wichita Medical Research and Education Foundation, Wichita, Kansas; Perdita Taylor-Zapata, MD, The Eunice Kennedy Shriver National Institute of Child Health and Human Development; June Lee, MD, PhD, The Eunice Kennedy Shriver National Institute of Child Health and Human Development. PTN Publications Committee: Chaired by Thomas P. Green, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
Disclaimer: All information and materials in the manuscript are original. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Additional Contributions: We thank Erin Campbell, MS, for her editorial assistance. Ms Campbell did not receive compensation for her assistance, apart from her employment at Duke Clinical Research Instititue.
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