Abstract:
Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or
plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with
artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs
to be defined better, particularly for important patient and parasite sub-populations.
Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual
pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated
Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors
that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov
and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on
study design, methodology and missing data.
Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21
studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations
(HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22
to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children
(<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than
adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7
lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The
highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low
transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated
with >98 % cure
