Chloroquine Dosing Recommendations for Pediatric COVID-19 Supported by Modeling and Simulation
Laurens F M Verscheijden1, Tjitske M van der Zanden1,2,3, Lianne P M van Bussel1
1Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Clinical Pharmacology and Therapeutics
|April 23, 2020
Summary
New dosing guidelines for chloroquine (CHQ) in pediatric COVID-19 patients are proposed. Age-adjusted doses aim to ensure safe and effective CHQ treatment for children, addressing suboptimal malaria dosing.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Pharmacology
- Infectious Disease Treatment
Background:
- Chloroquine (CHQ) is included in COVID-19 treatment guidelines, necessitating pediatric dosing information.
- Existing World Health Organization (WHO) pediatric dosing for malaria may be suboptimal for COVID-19 treatment.
- Lack of specific pediatric clinical trial data for CHQ in COVID-19 requires alternative dosing strategies.
Purpose of the Study:
- To establish evidence-based pediatric chloroquine (CHQ) doses for COVID-19 treatment.
- To compare CHQ exposure in pediatric populations versus adults using a physiologically-based pharmacokinetic (PBPK) model.
- To propose age-adjusted CHQ dosing regimens for children and adolescents infected with COVID-19.
Main Methods:
- Utilized a pre-existing physiologically-based pharmacokinetic (PBPK) model for chloroquine (CHQ).
- Simulated CHQ pharmacokinetics in adults and children, verifying against published data.
- Evaluated the standard adult COVID-19 CHQ dosage (44 mg/kg) across different pediatric age groups to assess exposure variations.
Main Results:
- Significant variations in CHQ exposure (AUC0-70h) were observed in children of different ages compared to adults when using a standard body-weight based dose.
- Proposed optimal total cumulative CHQ doses: 35 mg/kg (0-1 month), 47 mg/kg (1-6 months), 55 mg/kg (6 months-12 years), and 44 mg/kg (adolescents/adults).
- Revised age-adjusted doses, when re-introduced into the PBPK model, ensured CHQ exposure within 5% of the predicted adult value for each age group.
Conclusions:
- Age-adjusted chloroquine (CHQ) dosing is crucial for pediatric COVID-19 patients to prevent suboptimal or toxic drug exposure.
- The proposed dosing regimen supports safe and effective CHQ use in children across various age bands.
- Model-informed dose selection provides a science-based approach for pediatric dosing recommendations in the absence of clinical trial data.
Related Concept Videos
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion
149
In pediatric medicine, understanding the renal function and drug elimination nuances is crucial for administering safe and effective treatments. Newborns, in particular, display markedly slower renal functions than adults, profoundly affecting how drugs are cleared from their bodies. This slower drug clearance requires clinicians to extend the dosing intervals for many medications to prevent drug accumulation and toxicity while ensuring therapeutic efficacy.One key area where these adjustments...
149
01:29Drug Dosing: Infants and Children
177
Pediatric patient dosages diverge from adults due to disparities in body surface area, total body water, and extracellular fluid per kilogram of body weight. The dosing regimen considers the variations in pharmacokinetics and pharmacology across distinct age groups, encompassing preterm newborns, infants, young children, older children, and adolescents. Calculation of pediatric patient doses is predicated on determining body surface area, which exhibits a superior correlation with the child's...
177
01:17Pharmacokinetics in Pediatric Patients: Drug Distribution
194
Drug distribution in the pediatric population exhibits unique challenges and considerations due to the physiological differences between children, particularly neonates and infants, and adults. A crucial aspect of pediatric pharmacology is understanding how these differences impact the pharmacokinetics of various drugs, necessitating age-specific dosing strategies to ensure efficacy and safety.Neonates and infants have a higher total body water content, ~75%–90% of their body weight,...
194
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism
133
In pediatric care, understanding the nuances of hepatic drug metabolism is crucial, as it significantly differs from that of adults. This divergence is primarily due to the developmental stage of drug-metabolizing enzymes, which affects how medications are processed in the body. In neonates, for instance, the activity of Phase I enzymes—critical for the initial breakdown of drugs—is markedly reduced, functioning at just 20–40% of the levels seen in adults. This reduction poses...
133
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
174
Understanding the physiological differences in the pediatric population is crucial for effective pharmacotherapy. Neonates, infants, and children exhibit significant variations in gastric pH, gastric emptying time, intestinal transit time, and biliary function. These variations profoundly affect oral drug absorption, necessitating a nuanced approach to pediatric dosing.Neonates present with a unique physiological profile, having a gastric pH greater than 4 and faster and more irregular gastric...
174
01:25Drug Dosing in Renal Diseases: Dose Adjustments Based on Drug Clearance and Elimination Rate Constant
150
In patients with renal disease, dosage adjustments are necessary to maintain therapeutic plasma drug concentrations and prevent toxicity or subtherapeutic exposure. Renal impairment alters drug pharmacokinetics, especially in conditions like uremia, where changes such as prolonged elimination half-life and altered apparent volume of distribution can significantly affect drug disposition. These changes require careful modification of the dosing regimen to achieve the desired clinical...
150