Abstract | Importance: Objective: 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:
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Authors | Anil R Maharaj, Huali Wu, Christoph P Hornik, Stephen J Balevic, Chi D Hornik, P Brian Smith, Daniel Gonzalez, Kanecia O Zimmerman, Daniel K Benjamin Jr, Michael Cohen-Wolkowiez, Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee |
Journal | JAMA pediatrics
(JAMA Pediatr)
Vol. 174
Issue 10
Pg. e202422
(10 01 2020)
ISSN: 2168-6211 [Electronic] United States |
PMID | 32501511
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antiviral Agents
- remdesivir
- Adenosine Monophosphate
- Hydroxychloroquine
- Alanine
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Topics |
- Adenosine Monophosphate
(administration & dosage, analogs & derivatives, pharmacokinetics)
- Adolescent
- Adult
- Alanine
(administration & dosage, analogs & derivatives, pharmacokinetics)
- Antiviral Agents
(administration & dosage, pharmacokinetics)
- COVID-19
- Child
- Child, Preschool
- Coronavirus Infections
(drug therapy)
- Drug Administration Schedule
- Drug Dosage Calculations
- Female
- Humans
- Hydroxychloroquine
(administration & dosage, pharmacokinetics)
- Infant
- Infant, Newborn
- Male
- Models, Biological
- Pandemics
- Patient Simulation
- Pneumonia, Viral
(drug therapy)
- Therapies, Investigational
(methods)
- Young Adult
- COVID-19 Drug Treatment
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