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 (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.
More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data are needed to support off-label dosing, however for many drugs such data are either sparse or not representative. Physiologically-based pharmacokinetic (PBPK) models are increasingly used to study PK and guide dosing decisions. Building compound models to study PK requires expertise and is time-consuming. Therefore, in this paper, we studied the feasibility of predicting pediatric exposure by pragmatically combining existing compound models, developed e.g. for studies in adults, with a pediatric and preterm physiology model.
Obesity incidence is increasing among people with HIV. Doravirine is a recommended first-line antiretroviral drug in many countries with no data from people with obesity. This study investigates the exposure of doravirine 100 mg standard dose in obese versus normal weight patients using clinical data combined with physiologically based pharmacokinetic modelling. Results from both approaches showed an elevated doravirine exposure during obesity, yet within the safety range of doravirine with no need for dose modification.
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