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Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019

Educational Objective
To understand the proper dosage of hydroxychloroquine and remdesivir in children with coronavirus disease 2019
1 Credit CME
Key Points

Question  What are appropriate dosing strategies for hydroxychloroquine and remdesivir in children with coronavirus disease 2019?

Findings  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.

Meaning  To confirm the appropriateness of the proposed dosing schemes, prospective pharmacokinetic, safety, and efficacy studies in children are required.

Abstract

Importance  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.

Objective  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.

Interventions  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.

Results  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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Article Information

Corresponding Author: Michael Cohen-Wolkowiez, MD, PhD, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705 (michael.cohenwolkowiez@duke.edu).

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.

References
1.
Dong  Y , Mo  X , Hu  Y ,  et al.  Epidemiology of COVID-19 among children in China.   Pediatrics. 2020;e20200702. doi:10.1542/peds.2020-0702PubMedGoogle Scholar
2.
Lu  X , Zhang  L , Du  H ,  et al; Chinese Pediatric Novel Coronavirus Study Team.  SARS-CoV-2 infection in children.   N Engl J Med. 2020;382(17):1663-1665. doi:10.1056/NEJMc2005073PubMedGoogle ScholarCrossref
3.
Li  Q , Guan  X , Wu  P ,  et al.  Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.   N Engl J Med. 2020;382(13):1199-1207. doi:10.1056/NEJMoa2001316PubMedGoogle ScholarCrossref
4.
Huang  C , Wang  Y , Li  X ,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5PubMedGoogle ScholarCrossref
5.
Li  G , De Clercq  E .  Therapeutic options for the 2019 novel coronavirus (2019-nCoV).   Nat Rev Drug Discov. 2020;19(3):149-150. doi:10.1038/d41573-020-00016-0PubMedGoogle ScholarCrossref
6.
Ko  WC , Rolain  JM , Lee  NY ,  et al.  Arguments in favour of remdesivir for treating SARS-CoV-2 infections.   Int J Antimicrob Agents. 2020;55(4):105933. doi:10.1016/j.ijantimicag.2020.105933PubMedGoogle Scholar
7.
Colson  P , Rolain  JM , Raoult  D .  Chloroquine for the 2019 novel coronavirus SARS-CoV-2.   Int J Antimicrob Agents. 2020;55(3):105923. doi:10.1016/j.ijantimicag.2020.105923PubMedGoogle Scholar
8.
Raoult  D , Houpikian  P , Tissot Dupont  H , Riss  JM , Arditi-Djiane  J , Brouqui  P .  Treatment of Q fever endocarditis: comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine.   Arch Intern Med. 1999;159(2):167-173. doi:10.1001/archinte.159.2.167PubMedGoogle ScholarCrossref
9.
Biot  C , Daher  W , Chavain  N ,  et al.  Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.   J Med Chem. 2006;49(9):2845-2849. doi:10.1021/jm0601856PubMedGoogle ScholarCrossref
10.
Yao  X , Ye  F , Zhang  M ,  et al.  In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).   Clin Infect Dis. 2020:ciaa237. doi:10.1093/cid/ciaa237PubMedGoogle Scholar
11.
Tett  SE , Cutler  DJ , Day  RO , Brown  KF .  A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.   Br J Clin Pharmacol. 1988;26(3):303-313. doi:10.1111/j.1365-2125.1988.tb05281.xPubMedGoogle ScholarCrossref
12.
Furst  DE .  Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases.   Lupus. 1996;5(suppl 1):S11-S15. doi:10.1177/0961203396005001041PubMedGoogle ScholarCrossref
13.
Lim  HS , Im  JS , Cho  JY ,  et al.  Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax.   Antimicrob Agents Chemother. 2009;53(4):1468-1475. doi:10.1128/AAC.00339-08PubMedGoogle ScholarCrossref
14.
Martinez  MA .  Compounds with therapeutic potential against novel respiratory 2019 coronavirus.   Antimicrob Agents Chemother. 2020;64(5):e00399-20. doi:10.1128/AAC.00399-20PubMedGoogle Scholar
15.
Warren  TK , Jordan  R , Lo  MK ,  et al.  Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.   Nature. 2016;531(7594):381-385. doi:10.1038/nature17180PubMedGoogle ScholarCrossref
16.
Agostini  ML , Andres  EL , Sims  AC ,  et al.  Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease.   mBio. 2018;9(2):e00221-e18. doi:10.1128/mBio.00221-18PubMedGoogle ScholarCrossref
17.
European Medicines Agency (EMA). Summary on compassionate use: Remdesivir Gilead (Procedure No. EMEA/H/K/5622/CU). Published April 3, 2020. Accessed April 14, 2020. https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf
18.
Wang  M , Cao  R , Zhang  L ,  et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.   Cell Res. 2020;30(3):269-271. doi:10.1038/s41422-020-0282-0PubMedGoogle ScholarCrossref
19.
Maharaj  AR , Barrett  JS , Edginton  AN .  A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam.   AAPS J. 2013;15(2):455-464. doi:10.1208/s12248-013-9451-0PubMedGoogle ScholarCrossref
20.
Maharaj  AR , Edginton  AN .  Physiologically based pharmacokinetic modeling and simulation in pediatric drug development.   CPT Pharmacometrics Syst Pharmacol. 2014;3:e150. doi:10.1038/psp.2014.45PubMedGoogle Scholar
21.
Grimstein  M , Yang  Y , Zhang  X ,  et al.  Physiologically based pharmacokinetic modeling in regulatory science: an update from the U.S. Food and Drug Administration’s Office of Clinical Pharmacology.   J Pharm Sci. 2019;108(1):21-25. doi:10.1016/j.xphs.2018.10.033PubMedGoogle ScholarCrossref
22.
Mahmood  I , Tegenge  MA .  A comparative study between allometric scaling and physiologically based pharmacokinetic modeling for the prediction of drug clearance from neonates to adolescents.   J Clin Pharmacol. 2019;59(2):189-197. doi:10.1002/jcph.1310PubMedGoogle ScholarCrossref
23.
Dykstra  K , Mehrotra  N , Tornøe  CW ,  et al.  Reporting guidelines for population pharmacokinetic analyses.   J Pharmacokinet Pharmacodyn. 2015;42(3):301-314. doi:10.1007/s10928-015-9417-1PubMedGoogle ScholarCrossref
24.
Wickham  H . ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag; 2009.
25.
Wilke  CO . cowplot: Streamlined Plot Theme and Plot Annotations for 'ggplot2'. rdrr.io website. Accessed April 14, 2020. https://rdrr.io/cran/cowplot/
26.
Denney  W , Duvvuri  S , Buckeridge  C .  Simple, automatic noncompartmental analysis: the PKNCA R package.   J Pharmacokinet Pharmacodyn. 2015;42:S65-S65.Google Scholar
27.
Grothendieck  G , Zeileis  A .  zoo: S3 infrastructure for regular and irregular time series.   J Stat Softw. 2005;14(i06).Google Scholar
28.
Leong  R , Vieira  ML , Zhao  P ,  et al.  Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials.   Clin Pharmacol Ther. 2012;91(5):926-931. doi:10.1038/clpt.2012.19PubMedGoogle ScholarCrossref
29.
Brocks  DR , Skeith  KJ , Johnston  C ,  et al.  Hematologic disposition of hydroxychloroquine enantiomers.   J Clin Pharmacol. 1994;34(11):1088-1097. doi:10.1002/j.1552-4604.1994.tb01986.xPubMedGoogle ScholarCrossref
30.
McLachlan  AJ , Cutler  DJ , Tett  SE .  Plasma protein binding of the enantiomers of hydroxychloroquine and metabolites.   Eur J Clin Pharmacol. 1993;44(5):481-484. doi:10.1007/BF00315548PubMedGoogle ScholarCrossref
31.
Müller  F , König  J , Glaeser  H ,  et al.  Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine.   Antimicrob Agents Chemother. 2011;55(7):3091-3098. doi:10.1128/AAC.01835-10PubMedGoogle ScholarCrossref
32.
Fan  HW , Ma  ZX , Chen  J , Yang  XY , Cheng  JL , Li  YB .  Pharmacokinetics and bioequivalence study of hydroxychloroquine sulfate tablets in Chinese healthy volunteers by LC-MS/MS.   Rheumatol Ther. 2015;2(2):183-195. doi:10.1007/s40744-015-0012-0PubMedGoogle ScholarCrossref
33.
Tett  SE , Cutler  DJ , Day  RO .  Bioavailability of hydroxychloroquine tablets assessed with deconvolution techniques.   J Pharm Sci. 1992;81(2):155-159. doi:10.1002/jps.2600810211PubMedGoogle ScholarCrossref
34.
Li  XQ , Björkman  A , Andersson  TB , Gustafsson  LL , Masimirembwa  CM .  Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data.   Eur J Clin Pharmacol. 2003;59(5-6):429-442. doi:10.1007/s00228-003-0636-9PubMedGoogle ScholarCrossref
35.
McLachlan  AJ , Tett  SE , Cutler  DJ , Day  RO .  Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis.   Br J Rheumatol. 1994;33(3):235-239. doi:10.1093/rheumatology/33.3.235PubMedGoogle ScholarCrossref
36.
McLachlan  AJ , Tett  SE , Cutler  DJ , Day  RO .  Absorption and in vivo dissolution of hydroxycholoroquine in fed subjects assessed using deconvolution techniques.   Br J Clin Pharmacol. 1993;36(5):405-411. doi:10.1111/j.1365-2125.1993.tb00388.xPubMedGoogle ScholarCrossref
37.
Tett  SE , Cutler  DJ , Day  RO , Brown  KF .  Bioavailability of hydroxychloroquine tablets in healthy volunteers.   Br J Clin Pharmacol. 1989;27(6):771-779. doi:10.1111/j.1365-2125.1989.tb03439.xPubMedGoogle ScholarCrossref
38.
Cheung  KWK , van Groen  BD , Spaans  E ,  et al.  A comprehensive analysis of ontogeny of renal drug transporters: mRNA analyses, quantitative proteomics, and localization.   Clin Pharmacol Ther. 2019;106(5):1083-1092. doi:10.1002/cpt.1516PubMedGoogle ScholarCrossref
39.
Willmann  S , Höhn  K , Edginton  A ,  et al.  Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs.   J Pharmacokinet Pharmacodyn. 2007;34(3):401-431. doi:10.1007/s10928-007-9053-5PubMedGoogle ScholarCrossref
40.
Sciensano Epidemiology of Infectious Disease. Interim clinical guidance for adults with suspected or confirmed COVID-19 in Belgium, Version 7. sciensano website. Published April 7, 2020. Accessed April 14, 2020. https://epidemio.wiv-isp.be/ID/Documents/Covid19/COVID-19_InterimGuidelines_Treatment_ENG.pdf
41.
Michigan Medicine, University of Michigan. Inpatient guidance for treatment of COVID-19 in adults and children. Michigan Medicine, University of Michigan website. Accessed April 14, 2020. http://www.med.umich.edu/asp/pdf/adult_guidelines/COVID-19-treatment.pdf
42.
Kramer  NI , Krismartina  M , Rico-Rico  A , Blaauboer  BJ , Hermens  JL .  Quantifying processes determining the free concentration of phenanthrene in Basal cytotoxicity assays.   Chem Res Toxicol. 2012;25(2):436-445. doi:10.1021/tx200479kPubMedGoogle ScholarCrossref
43.
Postnikova  E , Cong  Y , DeWald  LE ,  et al.  Testing therapeutics in cell-based assays: factors that influence the apparent potency of drugs.   PLoS One. 2018;13(3):e0194880. doi:10.1371/journal.pone.0194880PubMedGoogle Scholar
44.
Liu  J , Cao  R , Xu  M ,  et al.  Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.   Cell Discov. 2020;6:16. doi:10.1038/s41421-020-0156-0PubMedGoogle ScholarCrossref
45.
Zhou  D , Dai  SM , Tong  Q .  COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.   J Antimicrob Chemother. 2020:dkaa114. doi:10.1093/jac/dkaa114PubMedGoogle Scholar
46.
Arnold  SLM , Buckner  F .  Hydroxychloroquine for treatment of SARS-CoV-2 infection? improving our confidence in a model-based approach to dose selection.   Clin Transl Sci. 2020;. doi:10.1111/cts.12797PubMedGoogle Scholar
47.
Balevic  SJ , Green  TP , Clowse  MEB , Eudy  AM , Schanberg  LE , Cohen-Wolkowiez  M .  Pharmacokinetics of hydroxychloroquine in pregnancies with rheumatic diseases.   Clin Pharmacokinet. 2019;58(4):525-533. doi:10.1007/s40262-018-0712-zPubMedGoogle ScholarCrossref
48.
Morita  S , Takahashi  T , Yoshida  Y , Yokota  N .  Population pharmacokinetics of hydroxychloroquine in Japanese patients with cutaneous or systemic lupus erythematosus.   Ther Drug Monit. 2016;38(2):259-267. doi:10.1097/FTD.0000000000000261PubMedGoogle ScholarCrossref
49.
Tegenge  MA , Mahmood  I .  Age- and bodyweight-dependent allometric exponent model for scaling clearance and maintenance dose of theophylline from neonates to adults.   Ther Drug Monit. 2018;40(5):635-641. doi:10.1097/FTD.0000000000000543PubMedGoogle ScholarCrossref
50.
Lee  JY , Vinayagamoorthy  N , Han  K ,  et al.  Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus.   Arthritis Rheumatol. 2016;68(1):184-190. doi:10.1002/art.39402PubMedGoogle ScholarCrossref
51.
Projean  D , Baune  B , Farinotti  R ,  et al.  In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation.   Drug Metab Dispos. 2003;31(6):748-754. doi:10.1124/dmd.31.6.748PubMedGoogle ScholarCrossref
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