Abstract
BackgroundA six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data.MethodsWithin a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa.ResultsC [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001).ConclusionMaintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.
Highlights
A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data
The fixed dose antimalarial combination of artemetherlumefantrine (A/L) is a promising and efficacious artemisinin-based combination treatment (ACT) that could play a key role in reducing the high mortality suffered by African children with Plasmodium falciparum malaria
The three day, six dose regimen of A/L is currently prioritized by the World Health Organization as a replacement for failing antimalarial monotherapies, notably chloroquine and sulfadoxine-pyrimethamine (SP)
Summary
A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. Taking a light (500 calories, 10 g fat) or 'normal' (1,000 calories, 20 g fat) meal within one hour either side of the first A/L dose increased lumefantrine bioavailability by a mean factor of 48% and 108%, respectively, compared to fluids alone[2]. In these volunteers, the relative bioavailability increased three-fold with the third and fourth doses compared to the first two doses because appetite improved rapidly in parallel with clinical recovery. In Thai patients, the lower and upper fifth percentile Cmax of the three day, six dose regimen were 1,100 and 19,800 ng/mL respectively, an eighteen-fold difference [3]
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