Small children and pregnant women may be underdosed with widely used antimalarial drug
Current recommended treatment regimens for the most widely used medicine for uncomplicated Plasmodium falciparum malaria may be sub-optimal for small children and pregnant women according to a study led by Prof. Joel Tarning, Head of Pharmacometrics at the WorldWide Antimalarial Resistance Network (WWARN) & Head of Clinical Pharmacology at the Mahidol Oxford Tropical Medicine Research Network (MORU).
Results published by PLOS Medicine show that young children and pregnant women have lower drug exposure levels of artemether-lumefantrine (AL), the most widely used antimalarial artemisinin-based combination therapy (ACT), and that revised dose regimens should be considered to optimise treatment of these vulnerable groups.
The World Health Organization estimates that malaria kills some 429,000 people every year, most of whom are small children living in poverty in sub-Saharan Africa. These results are of particular interest to global health policymakers, national governments and funders working towards global malaria elimination.
Pharmacokinetic-pharmacodynamic trials are generally small, and individual studies typically do not enrol enough young children or pregnant women to provide generalisable pharmacological results in these specific groups. To respond to this challenge, a team of researchers from across WWARN conducted a systematic review and meta-analysis using individual patient data from 26 clinical studies published between 1990-2013.
The researchers pooled relevant individual patient data on lumefantrine blood level measurements, clinical covariates, and outcomes data from 4,122 patients who had received artemether-lumefantrine. They developed a pharmacological model to understand how body weight, pregnancy, and baseline parasite density influence drug levels in patients, and therefore the therapeutic outcome.
Dr Frank Kloprogge, first author from University College London explains, "The results suggest that lumefantrine concentrations 7 days after starting standard 3-day artemether-lumefantrine treatment were 24.2% and 13.4% lower in children weighing less than 15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with older children and non-pregnant adults."
Prof Tarning, lead author, explains, "We developed a model to evaluate alternative dosing regimens and recommend that a longer 5-day regimen for both small children and pregnant women in their second and third trimester is the recommended adjustment for artemether-lumefantrine. A 5-day regimen also ensures that an additional asexual life cycle of parasites will be exposed to the partner drug artemether / dihydroartemisinin."
The authors note that these predictions are based on blood levels of the longer half-life partner drug in the combination (lumefantrine) but lack of data on the levels of the rapidly eliminated artemether prevented their ability to predict parasite killing rates and recrudescent infections. Further clinical trials are needed to demonstrate increased efficacy as well as adequate safety.
Dr Steven Kern, Deputy Director of Quantitative Sciences at the Bill & Melinda Gates Foundation concludes, "Maintaining an adequate exposure of these agents is critical to achieving therapeutic cure and should help to delay the spread of antimalarial drug resistance development in many areas of South-East Asia and beyond. The results will prolong the useful therapeutic life of this widely used antimalarial combination treatment and support the global drive to eliminate malaria."
The paper: Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis. Kloprogge F et al. PLOS Medicine. June 12, 2018.
The original Study Group details.