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Malaria can infect people of all ages, but young children with the disease fare particularly poorly and are often excluded from clinical trials of drug therapies.

Using a combination of kid-friendly blood sampling, clinical trials, and computer modeling, UCSF School of Pharmacy researchers have designed an effective new approach for preventing malaria in children: monthly doses of two drugs throughout the first few years of life, providing 95% protection.

The findings, published on November 18 in Nature Communications, offer new hope for the millions of children worldwide who suffer from repeated, and sometimes deadly, bouts with malaria.

“Malaria in young children is a big problem,” said Erika Wallender, MD, lead author of the study and a faculty member in the Department of Clinical Pharmacy. “Over time, adults develop some immunity, but children under two years of age have no resistance and are really vulnerable to disease or even death.”

Despite the availability of antimalarial drugs, bed nets, and insecticides targeting mosquitoes that spread the disease, malaria still causes 400,000 deaths each year. Two-thirds of the disease’s victims are children under five years old.

Wallender and her team focused their efforts on Uganda, a country with one of the highest malaria transmission rates in the world. Ninety-five percent of the country experiences perennial infections, and young Ugandan children contract up to six malaria infections per year.

Chemoprevention, or the routine use of medications in uninfected people, is one of the newest tools being used to fight malaria. The approach had already been tested in Ugandan children, with mixed results, but Wallender wondered whether it could be improved.

The researchers benefited from a library of 4,000 blood samples that were collected during a 2014 clinical trial of malaria chemoprevention in children. In this trial, 280 young children were treated with preventative antimalarials in the first few years of life, with their blood sampled during regular, routine visits to health clinics.

“For these types of studies, we rarely involve such young children,” Wallender said. “But collecting blood samples was made easier thanks to a test that minimizes trauma to the child.”

The test, developed by Clinical Pharmacy faculty member Francesca Aweeka, PharmD, and her team, uses a finger stick to collect a small drop of blood, just enough to assess the levels of drugs in a person’s body.

In 2016, Wallender’s team began measuring drug levels in these samples to better understand how various drug concentrations affect susceptibility to malaria. For children who did or didn’t contract malaria, what was the corresponding level of antimalarial in their blood? the team wondered. And what drug levels were needed to prevent malaria infection in all children?

The researchers combined data from the 2014 clinical trial samples with other data on the pharmacokinetics, or movement through the body, of these drugs, and used computer modeling to determine the dosages that maximized protection while minimizing toxicity and potential drug resistance.

The modeling showed that proactive administration of two antimalarials, dihydroartemisinin and piperaquine, to young children every four weeks provided 95 percent protection against malaria. The study also showed that malnourished children had lower drug levels in their blood than better-nourished children, leaving them more vulnerable to malaria—and suggesting where improvements could be made.

“The modeling work can really enhance the conclusions we draw from clinical trials,” said Wallender. “And in this case, it offers us the opportunity to improve the efficacy of dosing for all children, malnourished or not.”

The researchers concluded that age-based drug dosing, rather than the currently used weight-based regimen, would offer malnourished children the same benefits as other children. While body weight is lower in malnourished children, their organ size is more indicative of their ability to metabolize the drugs and is likely to be similar to better-nourished children of the same age. The issue is significant, since 25 percent of Ugandan children are underweight.

“We hope that this work will impact the use of and dosing for malaria chemoprevention, and also hope to provide a model for dose optimization of antimalarial drugs in vulnerable groups,” said Wallender. “But beyond defining a more effective regimen in children, our study really highlights the importance of malnourishment on the effectiveness of these therapies.”

By Tom Johnson written for the UCSF School of Pharmacy

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