Effect of Body Weight and Age on the Pharmacokinetics of Dihydroartemisinin: Food and Drug Administration Basis for Dose Determination of Artesunate for Injection in Pediatric Patients With Severe Malaria

Abstract

For treatment of severe malaria, the WHO recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe FDA’s rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

Artesunate inhibits airway remodeling in asthma via the MAPK signaling pathway

“…The operation method of Artesunate included oral, intravenous, rectal, and intramuscular injection. There was no significant difference in drug utilization rate among the different methods (Karbwang et al, 1994;van Agtmael et al, 1999;Kitabi et al, 2021). Oral artesunate might be the optimum usage on the basis of its likely higher convenience and economic benefit.…”

The Role of Nonapoptotic Programmed Cell Death — Ferroptosis, Necroptosis, and Pyroptosis — in Pancreatic Ductal Adenocarcinoma Treatment

“…Given that the development and approval of new drugs require substantial investment and time, drug repurposing has gained considerable attention in recent years ( 94 ). For instance, Artesunate has been approved by the FDA for the treatment of severe malaria ( 95 ); rapamycin is an FDA-approved immunosuppressant administered to organ transplantation patients ( 96 ); and Zalcitabine is a nucleoside reverse-transcriptase inhibitor approved by the FDA for HIV treatment ( 97 ). Recent studies have demonstrated their potential to induce ferroptosis and exhibit antitumor effects.…”

Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria

“…13,14 Based on this evidence from PK modeling of data from over 300 children and adults with severe malaria, the World Health Organization (WHO) has recommended parenteral ARS treatment doses of 3 mg/kg for patients weighing < 20 kg (i.e., over 90% of African children with severe malaria) since 2015; a 25% higher dose compared with the 2.4 mg/ kg recommended for children and adults that weigh > 20 kg. 15 Recently, the US Food and Drug Administration (FDA), based on simulated data by Kitabi et al, 16 has challenged this recommendation and suggested that younger children have higher drug exposures, and should therefore not receive an increased dose. Using a population PK model developed by Zaloumis et al, 14 Kitabi et al 16 simulated a virtual pediatric population with severe malaria using US Centers for Disease Control and Prevention (CDC) growth charts, 17,18 and predicted slower clearance and thus increased drug exposure (area under the concentration-time curve (AUC) over 0-12 hours) in children < 10 kg.…”

“…15 Recently, the US Food and Drug Administration (FDA), based on simulated data by Kitabi et al, 16 has challenged this recommendation and suggested that younger children have higher drug exposures, and should therefore not receive an increased dose. Using a population PK model developed by Zaloumis et al, 14 Kitabi et al 16 simulated a virtual pediatric population with severe malaria using US Centers for Disease Control and Prevention (CDC) growth charts, 17,18 and predicted slower clearance and thus increased drug exposure (area under the concentration-time curve (AUC) over 0-12 hours) in children < 10 kg. Importantly their simulations assumed that weight (and age) are independent of another important covariate, hemoglobin, which is not the case in malaria endemic countries.…”

“…Monte Carlo simulations using the PK parameters from the current analysis of the REACH study as well as those derived from studies of Hendriksen et al 13 (70 Tanzanian children treated with intra-muscular ARS-2.4 mg/kg) and Zaloumis et al 14 (223 patients receiving ARS intravenously-2.4 mg/kg) were used to obtain representative population estimates of the exposure levels (area under the DHA concentrationtime curve from time point 0 to 12 hours) at different body weights and under different dosing loads in the virtual population. More specifically, we ran 1,000 simulations at each 1 kg interval from 3 to 40 kg with different doses of ARS: the 2.4 mg/kg dose of ARS for all ages as currently endorsed by the FDA 16 and the weight-based dose, 3 mg/kg for children < 20 kg, and 2.4 mg/kg for heavier patients, currently recommended by the WHO. 15 We also considered an age-related enzyme-maturation effect which accounts for the reduced ability of younger children to metabolize DHA (see Supplementary Information S2).…”