The effect of dose on the antimalarial efficacy of artemether–lumefantrine: a systematic review and pooled analysis of individual patient data

Abstract

SummaryBackground-Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malariaendemic settings.Methods-We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 Findings-We included 61 studies done between Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose).Interpretation-The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups.Funding-Bill & Melinda Gates Foundation. IntroductionArtemisinin-based combination therapies are the first-line treatment for uncomplicated Plasmodium falciparum malaria in most malaria-endemic countries, 1 and they have been advocated to counter the threat of antimalarial drug resistance by delaying its emergence and spread. 2 As such, artemisinin-based combination therapies are a key component of malaria elimination efforts. 3The combination of artemether and lumefantrine was originally introduced as a four-dose regimen that proved to be efficacious in studies done in China, 4 Africa, 5 and India; 6 however, after detailed pharmacokinetic-pharmacodynamic assess...

Open-label trial on efficacy of artemether/lumefantrine against the uncomplicated <em>Plasmodium falciparum</em> malaria in Metema district, Northwestern Ethiopia

“…This fast action of AL was already reported in studies conducted elsewhere in Ethiopia11,12,20 and Tanzania 24. The emerging resistance to artemisinins on the Thailand–Cambodian border26,27 has been characterized by the slow parasite clearance in vivo and the increased day 3 positive cases 9,12,28,29. The day 3 parasitemia on blood smear is a good predictor of the forthcoming failure in Coartem ® therapy in the areas of low and moderate transmission 9.…”

Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger

“…However, the WWARN found that the risk of treatment failure with AL was greatest in children underweight-for-age (i.e., suffering from global malnutrition) aged 1–3 years in Africa [18]. In our study, AL was administered concomitantly with RUTF in SAM children, which might have contributed to an improved drug absorption in this group.…”

“…Though not correlated with a higher risk of treatment failure or reinfection in our study, the low concentration achieved in SAM and young children is still a concern, as sub-optimal exposure to antimalarials is the first step to the emergence of parasite resistance [35]. The question of adapting dosing strategies in younger and malnourished children should be investigated further [18]. The ongoing PK modelling of our data will include simulation of different AL dosing scenarios to assess their effect on lumefantrine PK profile.…”

“…Early vomiting within half an hour after dosing was more frequent in SAM children (37.4 % vs. 20.7 %), and its frequency doubled when the dose-weight exceeded the toxicity threshold of 100 mg/kg [18]: (44/100 (44 %) of patients receiving more than 100 mg/kg reported vomiting vs. 60/297 (20.2 %) for those receiving a lower dose-weight, P  < 0.0001).…”

“…A recent meta-analysis conducted by the Worldwide Antimalarial Resistance Network (WWARN) indicated that the risk of treatment failure with artemether-lumefantrine (AL) was greatest in children suffering from global malnutrition; however, it did not include SAM children nor did it measure drug concentration [18]. …”