A common antimalarial treatment has less effect in children with severe malnutrition

The researchers found that severe malnutrition was badociated with lower exposure to the antimalarial drug, lumefantrine, in children treated with artemether-lumefantrine, the most common treatment for uncomplicated falciparum malaria. The study, which is the first to specifically address this topic, was published in Clinical and therapeutic pharmacology. It urgently calls for further research on optimized dosing regimens for malnourished children.

Children under five are particularly vulnerable to malaria infection, with 61% of all malaria deaths worldwide. Malnourished children have an even greater risk of contracting and dying from malaria, which is strongly badociated with poverty.

Modified physiology in malnourished children can alter the absorption and distribution of antimalarials in the body. For example, the absorption and elimination of drugs could be reduced in these children. Despite this, little research has been conducted on the efficacy of treatments in this particular group.

Malnourished children and other groups of vulnerable patients, such as pregnant women and very young children, are often excluded from clinical trials because they are not the main target group, they are difficult to recruit in large numbers and their participation can raise specific ethical concerns. The data that exists in malnourished children are so far contradictory, as highlighted by a recently published systematic study by the Global Network for the Control of Antimalarial Drug Resistance (WWARN).

Artemether-lumefantrine, an artemisinin-based combination therapy, is the most widely used antimalarial drug in the world and is recommended by the World Health Organization. Exposure to lumefantrine, drug concentrations in the blood after the administration of treatment, would have been lower in children than in adults. Children currently follow the same dosing regimen as adults, namely artemether-lumefantrine, twice daily for three days.

This study conducted in collaboration with Epicenter, Médecins Sans Frontières, the University of Cape Town, the Malaria Research and Training Center in Mali and the Mahidol-Oxford Research Unit on Tropical Medicine (MORU) and the Ministry of Health of Niger aimed at the pharmacokinetic (pharmacokinetic) and pharmacodynamic (PM) properties of lumefantrine in severely malnourished children were previously poorly defined. The badysis included data from a clinical trial conducted in two hospitals in Mali and Niger, badyzing exposure to lumefantrine for the treatment of uncomplicated falciparum malaria in 131 malnourished children. severe, compared to 226 children without malnutrition. This is the largest cohort of patients in this type of badysis so far.

Key measures of malnutrition were collected, including weight / height ratio, arm circumference, and nutritional edema. These measures are not routinely collected in clinical trials on malaria, a practice that is expected to change to better understand the systematic under-exposure of antimalarial drugs in children due to malnutrition.

We have developed a pharmacokinetic and pharmacodynamic model to describe the pharmacological properties of lumefantrine in these children. The absorption, distribution, metabolism or elimination of the drug may be affected by the nutritional status of the children. The effects of malnutrition on pharmacological parameters have been carefully studied and evaluated. "

Dr. Palang Chotsiri, researcher at MORU and first author of the study

The researchers found that:

• Severely malnourished children were, on average, 19.2% less exposed to lumefantrine
• All children were significantly less exposed to drugs than adults
• All measures of malnutrition were correlated with reduced absorption of lumefantrine, with the circumference of the lower mid-thigh being the most important factor badociated with poor absorption.
• Less exposure to lumefantrine also resulted in an increased risk of treatment failure and new infection with malaria (P. falciparum) during the follow-up period.

Professor Joel Tarning, head of the WWARN Pharmacometrics group who led the study, said:

The badociations between malnutrition and the efficacy of antimalarials present serious gaps in knowledge. This study provides essential information. Children suffering from malnutrition are more severely affected by malaria and have lower levels of antimalarial drugs in their body after standard treatment. This requires further study so that we can better treat these patients. By collaborating with our partners such as Epicenter, MSF, MTRC, MORU and the University of Cape Town, we can fill these gaps in research. "

Dr. Rebecca Grais, Research Director, Epicenter, the epidemiology and research satellite of Doctors Without Borders, said:

This study is essential to improve treatment protocols for this group of very vulnerable children. Children with both severe acute malnutrition and malaria are most in need of care. "

The researchers then used the model to evaluate three different dosing regimens to determine if this could improve exposure to lumefantrine. The dosage regimen has been increased, intensified and expanded. It has been found that an increased dosage would not increase the exposure due to the limited ability of severely malnourished children to absorb the drug. However, intensified treatment (three times a day for three days) and prolonged treatment (twice a day for five days) would result in equivalent exposures in both groups, thus raising the level for children with severe malnutrition.

The researchers recommend continuing work to study optimized dosing regimens to improve antimalarial treatments in malnourished children.