Chloroquine Dosing Recommendations for Pediatric COVID-19 Supported by Modeling and Simulation.

ABSTRACT

As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID-19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration-time curve from zero to 70 hours (AUC0-70h ) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-based alternative to recommend pediatric dosing when pediatric clinical trial data is absent.