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 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 (AUC 0-70h ) 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.With coronavirus disease 2019 (COVID-19) spreading rapidly across the globe, effective drug treatment is desperately needed. Based on Chinese population data, < 1% of the infected cases were children below the age of 10 years and clinical symptoms in these patients were milder compared with adults. 1 However, it is unknown how such numbers will evolve when a higher percentage of the entire world population with diverse ethnic and socioeconomical backgrounds is infected.

Pharmacokinetics under the COVID-19 storm!

“…The current situation surrounding COVID-19 requires fast decision in clinical trial design with limited information, consequently, resulting in a potentially higher risk or lower benefit. A few such examples include higher incidence of side effects for chloroquine and lack of benefit from lopinavir and ritonavir combination therapy [32,33]. COVID patients who received chloroquine with azithromycin experienced QTc prolongation, which may be attributed to PK or PD changes in target tissues as a result of DDI.…”

COVID‐19: A Defining Moment for Clinical Pharmacology?

“…However, clinical pharmacologists have a wealth of knowledge about approved drugs, many of which are currently in clinical trials for repurposing. This knowledge can be harnessed and translated immediately to optimize dosing and treatment regimens: Absorption, distribution, metabolism, and pharmacokinetics; Pharmacokinetics in special populations and the role of factors such as age (including pediatrics 5 and geriatrics), gender, ethnicity, morphometry, disease, and organ function; Drug–drug interactions (DDIs): infectious diseases are often best treated with more than one drug, and several potential combination therapies have already been proposed for COVID‐19 2 . In addition, age is associated with concomitant medications, which may cause DDIs with COVID‐19 drugs, especially those commonly used in older people; Pharmacogenomics and precision medicine; Relationship between pharmacokinetics and pharmacodynamics (biomarker) response; Relationship between exposure and adverse events 6,7 …”

Systematic Review and Pharmacological Considerations for Chloroquine and Its Analogs in the Treatment for COVID-19

“…As a traditional antimalaria agent, WHO has released guidelines for the treatment of malaria; however, there was little content concerning the efficacy and safety of CQ treatment in pediatrics. Laurens et al reported CQ dosing recommendation for pediatrics based on PBPK modeling: 35 mg/kg (CHQ base) for children 0 to 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 (Verscheijden et al, 2020). With cautions that the lethal toxicity in children has been reported as unintentional overdoses of~35-100 mg/kg of CQ (base) in a single dose (Verscheijden et al, 2020).…”

“…Laurens et al reported CQ dosing recommendation for pediatrics based on PBPK modeling: 35 mg/kg (CHQ base) for children 0 to 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 (Verscheijden et al, 2020). With cautions that the lethal toxicity in children has been reported as unintentional overdoses of~35-100 mg/kg of CQ (base) in a single dose (Verscheijden et al, 2020). Currently, diagnosis and treatment recommendation for pediatric COVID-19 released by China National Clinical Research Center for Child Health was not recommended CQ in pediatrics.…”