Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria
Issued Date
2023-01-01
Resource Type
ISSN
00099236
eISSN
15326535
DOI
Scopus ID
2-s2.0-85171292418
Pubmed ID
37666798
Journal Title
Clinical Pharmacology and Therapeutics
Rights Holder(s)
SCOPUS
Bibliographic Citation
Clinical Pharmacology and Therapeutics (2023)
Suggested Citation
Haghiri A., Price D.J., Fitzpatrick P., Dini S., Rajasekhar M., Fanello C., Tarning J., Watson J., White N.J., Simpson J.A. Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria. Clinical Pharmacology and Therapeutics (2023). doi:10.1002/cpt.3041 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/90174
Title
Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria
Other Contributor(s)
Abstract
The majority of deaths from malaria are in young African children. Parenteral artesunate (ARS) is the first-line treatment for severe falciparum malaria. Since 2015, the World Health Organization has recommended individual doses of 3 mg/kg for children weighing < 20 kg. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic (PK) modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of ARS intravenously. Bayesian hierarchical modeling and a two-compartment parent drug-metabolite PK model for ARS were used to describe the population PKs of ARS and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first-dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous ARS do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower ARS dose recommendation as parenteral ARS is an extremely safe and well-tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.