Frank KloproggeLesley WorkmanSteffen BorrmannMamadou TékétéGilbert LefèvreKamal HamedPatrice PiolaJohan UrsingPoul Erik KofoedAndreas MårtenssonBilly NgasalaAnders BjörkmanMichael AshtonSofia Friberg HietalaFrancesca AweekaSunil ParikhLeah MwaiTimothy M.E. DavisHarin KarunajeewaSam SalmanFrancesco ChecchiCarole FoggPaul N. NewtonMayfong MayxayPhilippe DeloronJean François FaucherFrançois NostenElizabeth A. AshleyRose McGreadyMichele van VugtStephane ProuxRic N. PriceJuntra KarbwangFarkad EzzetRajesh BakshiKasia StepniewskaNicholas J. WhitePhilippe J. GuerinKaren I. BarnesJoel TarningPharmetheus ABMuhimbili University of Health and Allied SciencesBandim Health ProjectInstitut Pasteur du CambodgeKenya Medical Research InstituteShoklo Malaria Research UnitUniversity of Western AustraliaLondon School of Hygiene &amp; Tropical MedicineUniversite Paris DescartesWalter and Eliza Hall Institute of Medical ResearchUniversity of OxfordDanderyd HospitalMenzies School of Health ResearchUniversity of PortsmouthUniversity of California, San FranciscoCentre de Recherches Pour Le Développement InternationalUCLKarolinska University HospitalUniversität TübingenGöteborgs UniversitetCHU de LimogesEpicentreMahidol UniversityKarolinska InstitutetNagasaki UniversityNovartis International AGYale UniversityCharles Darwin UniversityUppsala UniversitetAmsterdam UMC - University of AmsterdamUniversity of Cape TownKolding SygehusWorldWide Antimalarial Resistance NetworkUniversity of SciencesNovartis PharmaceuticalsWellcome Trust Research UnitWorldWide Antimalarial Resistance NetworkMyanmar Oxford Clinical Research UnitWorld Wide Antimalarial Resistance Network (WWARN)-Asia Regional CentreWorldWide Antimalarial Resistance NetworkAfya Research AfricaUniversity of Health Sciences2019-08-282019-08-282018-06-01PLoS Medicine. Vol.15, No.6 (2018)15491676154912772-s2.0-85049503104https://repository.li.mahidol.ac.th/handle/20.500.14594/46658© 2018 Kloprogge et al. http://creativecommons.org/licenses/by/4.0/ Background: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. Methods and findings: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Conclusions: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.Mahidol UniversityMedicineArticleSCOPUS10.1371/journal.pmed.1002579