Elizabeth A. AshleyFrancesca AweekaKaren I. BarnesQuique BassatSteffen BorrmannPrabin DahalTimothy M.E. DavisMey Bouth DenisAbdoulaye A. DjimdeJean François FaucherBlaise GentonPhilippe J. GuérinKamal HamedEva Maria HodelLiusheng HuangVincent JullienHarin A. KarunajeewaJean René KiechelPoul Erik KofoedGilbert LefèvreNiklas Lindegardh LindegardhAndreas MårtenssonMayfong MayxayRose McgreadyClarissa MoreiraPaul N. NewtonBilly E. NgasalaFrancois NostenChristian NsanzabanaSunil ParikhPatrice PiolaRic N. PricePascal RingwaldLars RomboBirgit SchrammCarol Hopkins SibleyKasia StepniewskaJoel TarningJohan UrsingMichele Van VugtNicholas J. WhiteLesley J. WorkmanPhilippe DeloronKevin MarshShoklo Malaria Research UnitMahidol UniversityUniversity of California, San FranciscoWorldWide Antimalarial Resistance Network (WWARN)University of Cape TownInstituto de Salud Global de BarcelonaCentro de Investigação em Saúde de Manhiça (CISM)Wellcome Trust Research Laboratories NairobiUniversitat TubingenNuffield Department of Clinical MedicineUniversity of Western AustraliaIRD Institut de Recherche pour le DeveloppementUniversite Paris DescartesNational Center for ParasitologyOrganisation Mondiale de la SanteUniversity of Bamako Faculty of Medicine, Pharmacy and Odonto-StomatologyHopital Jean MinjozSwiss Tropical and Public Health Institute (Swiss TPH)Centre Hospitalier Universitaire VaudoisNovartis Pharmaceuticals CorporationLiverpool School of Tropical MedicineDrugs for Neglected Diseases InitiativeSyddansk UniversitetKolding SygehusNovartis International AGKenya Medical Research InstituteKarolinska InstitutetWellcome TrustMuhimbili University of Health and Allied SciencesYale Schools of Public Health and MedicineDepartment of Clinical PharmacologyInstitut Pasteur de MadagascarMenzies School of Health ResearchUppsala UniversitetEpicentreUniversity of Washington, SeattleUniversity of Amsterdam2018-11-232018-11-232015-09-18BMC Medicine. Vol.13, No.1 (2015)174170152-s2.0-84942087456https://repository.li.mahidol.ac.th/handle/20.500.14594/36324© 2015 WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group. 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 rates (if parasitemia <135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.Mahidol UniversityMedicineArticleSCOPUS10.1186/s12916-015-0456-7