Antimalarial dose optimisation helps to improve patient treatment results

Artemether-lumefantrine, also known by the trade names Coartem and Riamet, is the most widely used artemisinin-based combination therapy (ACT). It was the first ACT to be pre-approved by the World Health Organization in 2004. AL is recommended as first-line treatment for uncomplicated malaria caused by Plasmodium falciparum in a majority of the sub-Saharan African countries and also by the United States Centers for Disease Control and Prevention (CDC). As such, it accounts for three quarters of all ACTs administered to patients in an estimated 80 countries worldwide.

Optimising the dose of malaria treatments is critical in containing the emergence and spread of antimalarial drug resistance. Children can be at risk of being over-dosed because of weight and age-based banding, or sub-optimally dosed when antimalarials such as AL are given as tablets, or fractions of tablets, rather than specific paediatric formulations.

“This important report brings together the data from a wide range of clinical trials over the last decade,” said Dr Tim Wells, CSO of Medicines for Malaria Venture. “The collected data confirm that artemether-lumefantrine continues to be tremendously effective in curing malaria. Even smaller children achieve a highly effective cure rate. The data will help guide policy makers on whether there is a need for some fine tuning of the antimalarial treatment guidelines for the very smallest children, or in malnutrition.”

Overall, the results of the pooled analysis suggest that AL continues to be efficacious with an overall cure rate of 97.6 per cent. However, the latest results published in the Lancet Infectious Diseases also show that children in Asia weighing 10–15 kg who receive lower doses of lumefantrine have lower drug performance results, and malnourished children in Africa were at risk of treatment failure.

“AL continues to work really well in the majority of malaria endemic countries, however, our preliminary evidence suggests that young children receiving lower doses of this treatment are not being cured as quickly as other patient groups,” says Professor Ric Price, Head of the Clinical Group at WWARN and Principal Research Fellow, Menzies School of Health Research, Darwin, Australia. “We need to undertake more research to confirm whether adjustments are needed for specific vulnerable groups, particularly in areas of Africa at risk of famine and the greater Mekong region in Asia, where multidrug resistance is highly prevalent.”

The research team pooled data from 61 trials, including 14,327 individual results from patients treated with AL between 1998 and 2012. They investigated the effects that AL drug dosing regimens are having on different population groups in a wide range of malaria endemic settings.

Previous dosing analysis from the Dihydroartemisinin-Piperaquine (DP) Dose Impact Study Group found that small children who receive a lower doses of DP, are slower to respond to treatment, less likely to kill all the parasites in their bodies, and more likely to have malaria recurrence a few weeks later. The study concluded that policy makers should consider reviewing current dosing recommendations for DP, particularly for vulnerable groups such as young children.

“Optimal dosing of antimalarial drug regimens is vital to sustaining the efficacy of our best antimalarial combinations, and to help to contain the spread of drug resistance,” says Dr. Christian Nsanzabana, WWARN Scientific Coordinator. “Despite these latest findings there is no evidence to suggest that increasing the dose of AL in these groups of children will necessarily result in higher cure rates, and higher drug concentrations in the blood, as the absorption of lumefantrine at this dose is reported to be at saturation point. We need more data to confirm the best treatment options for vulnerable patient populations.”

”These results are reassuring for the millions of patients treated with artemether-lumefantrine for uncomplicated malaria each year. They show that artemether-lumefantrine remains an effective antimalarial treatment,” says Dr. Kamal Hamed, Novartis Pharmaceuticals Corporation. “Systematic and powerful pooled analyses such as this one help to better evaluate outcomes in specific subpopulations that are traditionally missed by much smaller clinical trials.”

A WWARN ASAQ Study Group is also currently investigating if patients are receiving optimal dose regimens for the antimalarial drug, artesunate-amodiaquine. Publication of these results are expected by early April 2015.

Publication details:

Worldwide Antimalarial Resistance Network (WWARN) AL Does Impact Study Group. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. The Lancet Infectious Diseases 2015; D-14-00566R1; DOI 10.1016 S1473-3099 (15)70024-1

Related publications:

The Worldwide Antimalarial Resistance Network (WWARN) DP Study Group (2013) The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data. PLOS Med 10(12): e1001564. DOI:10.1371/journal.pmed.1001564