New artesunate combination safe for use in recurrent malaria

By C. Vidya Shankar MD

NEW YORK (Reuters Health) - Pyronaridine-artesunate, a new oral antimalarial combination, can be reused for malaria recurrences without toxicity, according to a study from West Africa.

These findings are significant as the combination is currently approved for use only once for each patient and not repeated because of reports of hepatotoxicity, lead author Dr. Abdoulaye A. Djimde, from the University of Science, Techniques and Technologies of Bamako, Mali, told Reuters Health by email.

The current recommendations do not allow this combination to be used for malaria control programs in sub-Saharan Africa because many patients experience multiple episodes of malaria.

"These data will support the registration of this new treatment for use in countries in sub-Saharan Africa, where the death toll of malaria is the greatest in the world," Dr. Djimde pointed out.

Their report was a sub-study analysis of the ongoing randomized West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) conducted in Mali, Burkina Faso, and Guinea. The phase 3b/4 trial enrolled 1686 patients aged older than six months with confirmed uncomplicated Plasmodium malariae, falciparum or ovale infection and analyzed the toxicity profile with recurrent use of pyronaridine-artesunate combination. Equal numbers were allotted to pyronaridine-artesunate and artemether-lumefantrine groups.

Pyronaridine-artesunate once daily for three days and artemether-lumefantrine combination twice daily for three days were given orally, dosed according to body weight. Patients were treated with the same antimalarial combination for recurrent attacks during a two-year period.

Treatment for a new episode after 28 days was considered as retreatment. Hepatotoxicity was defined as a five-fold rise in alanine aminotransferase levels or a three-fold rise in alanine aminotransferase or aspartate aminotransferase and a two-fold rise in total bilirubin after treatment.

"Pyronaridine-artesunate re-treatment did not increase overall safety risk based on adverse event frequencies, laboratory values, or electrocardiogram findings," the researchers reported online October 23 in the Lancet Infectious Diseases.

In the pyronaridine-artesunate group, 42% reported adverse effects after first treatment and 37% after retreatment, while hepatotoxicity with first exposure and re-treatment were similar (0.19% versus 0.54%). In the lumefantrine group 45% developed adverse events after the first dose and 40% after retreatment. Hepatotoxicity was less than 1%. All adverse reactions were transient and resolved completely.

Efficacy was similar in both groups, the research team observed, with the adequate clinical and parasitological response (ACPR) greater than 95% after 28 days and 91% after 42 days in both groups.

"Drug-induced liver injury is one of the most common reasons for failure of new compounds during clinical development," Dr. Sabine Belard, of Charite University, Berlin, Germany, and Florian Kurth, from the Institute for Tropical Medicine, Tubingen, Germany, wrote in a related commentary. Though the findings are "highly reassuring," important "target populations" for malaria, including those with liver disease or HIV, were excluded, and few children were included in the study, they pointed out.

"Only a few artemisinin-based combination therapies (ACT) are available to treat malaria. Having several ACTs available for treatment at the same time, or alternately, would slow down the development of drug resistance." Dr. Djimde emphasized.

"Therefore adding this new ACT, artesunate-pyronaridine, to the few that are available will greatly improve not only the effective treatment of malaria in the malaria-endemic countries of sub-Saharan Africa but also prolong the lifespan of these efficacious drugs," he concluded.

This research had a number of supporters. Twenty-three coauthors reported relevant relationships.

SOURCE: http://bit.ly/1OzNX8a and http://bit.ly/1OzO1Vr

Lancet Infect Dis 2015

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