{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:42:15Z","timestamp":1787236935051,"version":"build-2736575974"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01 HD068174"],"award-info":[{"award-number":["R01 HD068174"]}]},{"name":"UCSF Center for AIDS Research","award":["P30 AI022763"],"award-info":[{"award-number":["P30 AI022763"]}]},{"name":"Wilbur Downs Fellowship"},{"name":"National Institute of General Medical Sciences of the National Institutes of Health"},{"name":"American Foundation for Pharmaceutical Education Pre-Doctoral Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy in Sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a prospective, randomized, open-label pharmacokinetic\/pharmacodynamic study of extended duration AL in children with malaria in high-transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin, and lumefantrine over 42-day clinical follow-up. Primary outcomes were (1) comparative pharmacokinetic parameters between regimens and (2) recurrent parasitemia analyzed as intention-to-treat.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 177 children aged 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (P &amp;lt; .001). A predefined day 7 lumefantrine threshold of 280 ng\/mL was strongly predictive of recurrence risk at 28 and 42 days (P &amp;lt; .001). Kaplan\u2013Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3- and 5-day regimens. No significant toxicity was seen with the extended regimen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high-transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk, and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov number NCT03453840.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciac783","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T11:55:30Z","timestamp":1663674930000},"page":"443-452","source":"Crossref","is-referenced-by-count":12,"title":["The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial"],"prefix":"10.1093","volume":"76","author":[{"given":"Meghan E","family":"Whalen","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, University of California-San Francisco, San Francisco General Hospital , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Kajubi","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Orukan","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenzie","family":"Colt","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liusheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of California-San Francisco, San Francisco General Hospital , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacey","family":"Richards","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaicheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norah","family":"Mwebaza","sequence":"additional","affiliation":[{"name":"Infectious Disease Research Collaboration , Kampala , Uganda"},{"name":"Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca T","family":"Aweeka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, University of California-San Francisco, San Francisco General Hospital , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9411-5180","authenticated-orcid":false,"given":"Sunil","family":"Parikh","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health , New Haven, Connecticut , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"2023020817103997800_ciac783-B1","author":"World Health Organization","year":"2021"},{"key":"2023020817103997800_ciac783-B2","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","article-title":"Evidence of artemisinin-resistant malaria in Africa","volume":"385","author":"Balikagala","year":"2021","journal-title":"N Engl J Med"},{"key":"2023020817103997800_ciac783-B3","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/S1473-3099(21)00142-0","article-title":"Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study","volume":"21","author":"Uwimana","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"2023020817103997800_ciac783-B4","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/S1473-3099(21)00692-7","article-title":"Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial","volume":"22","author":"Peto","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"2023020817103997800_ciac783-B5","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/S1473-3099(22)00209-2","article-title":"Is triple artemisinin-based combination therapy necessary for uncomplicated malaria?","volume":"22","author":"Rasmussen","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"2023020817103997800_ciac783-B6","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1097\/QCO.0000000000000766","article-title":"Artemisinin and multidrug-resistant Plasmodium falciparum \u2013 a threat for malaria control and elimination","volume":"34","author":"Dhorda","year":"2021","journal-title":"Curr Opin Infect Dis"},{"key":"2023020817103997800_ciac783-B7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1001984","article-title":"The community as the patient in malaria-endemic areas: preempting drug resistance with multiple first-line therapies","volume":"13","author":"Boni","year":"2016","journal-title":"PLoS Med"},{"key":"2023020817103997800_ciac783-B8","author":"World Health Organization","year":"2021"},{"key":"2023020817103997800_ciac783-B9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.2165\/00003088-200039040-00002","article-title":"Pharmacokinetics of artemisinin-type compounds","volume":"39","author":"Navaratnam","year":"2000","journal-title":"Clin Pharmacokinet"},{"key":"2023020817103997800_ciac783-B10","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1124\/dmd.30.9.1005","article-title":"Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases","volume":"30","author":"Ilett","year":"2002","journal-title":"Drug Metab Dispos"},{"key":"2023020817103997800_ciac783-B11","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1046\/j.1365-2125.1998.00830.x","article-title":"Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients","volume":"46","author":"Ezzet","year":"1998","journal-title":"Br J Clin Pharmacol"},{"key":"2023020817103997800_ciac783-B12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.2165\/00044011-199918060-00006","article-title":"Clinical pharmacokinetics of artemether and lumefantrine (Riamet)","volume":"18","author":"Lefevre","year":"1999","journal-title":"Clin Drug Invest"},{"key":"2023020817103997800_ciac783-B13","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1186\/1475-2875-11-435","article-title":"Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda","volume":"11","author":"Jagannathan","year":"2012","journal-title":"Malar J"},{"key":"2023020817103997800_ciac783-B14","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1097\/QAD.0000000000000497","article-title":"Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial","volume":"28","author":"Kamya","year":"2014","journal-title":"AIDS"},{"key":"2023020817103997800_ciac783-B15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.pt.2007.11.008","article-title":"Antimalarial dosing regimens and drug resistance","volume":"24","author":"Barnes","year":"2008","journal-title":"Trends Parasitol"},{"key":"2023020817103997800_ciac783-B16","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.2165\/00003088-200645110-00003","article-title":"Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations","volume":"45","author":"Bartelink","year":"2006","journal-title":"Clin Pharmacokinet"},{"key":"2023020817103997800_ciac783-B17","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1086\/503423","article-title":"Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria","volume":"42","author":"Price","year":"2006","journal-title":"Clin Infect Dis"},{"key":"2023020817103997800_ciac783-B18","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1128\/AAC.00679-09","article-title":"Pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in children in Kampala, Uganda","volume":"54","author":"Mwesigwa","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2023020817103997800_ciac783-B19","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00228-010-0851-0","article-title":"A systematic review of pharmacokinetics studies in children with protein-energy malnutrition","volume":"66","author":"Oshikoya","year":"2010","journal-title":"Eur J Clin Pharmacol"},{"key":"2023020817103997800_ciac783-B20","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/toxsci\/66.2.185","article-title":"Evaluation of child\/adult pharmacokinetic differences from a database derived from the therapeutic drug literature","volume":"66","author":"Ginsberg","year":"2002","journal-title":"Toxicol Sci"},{"key":"2023020817103997800_ciac783-B21","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1002579","article-title":"Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamic meta-analysis","volume":"15","author":"Kloprogge","year":"2018","journal-title":"PLoS Med"},{"key":"2023020817103997800_ciac783-B22","doi-asserted-by":"crossref","first-page":"5306","DOI":"10.1128\/AAC.05136-11","article-title":"Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria","volume":"55","author":"Salman","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2023020817103997800_ciac783-B23","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1093\/infdis\/jiw338","article-title":"Population pharmacokinetics and pharmacodynamics of lumefantrine in young Ugandan children treated with artemether-lumefantrine for uncomplicated malaria","volume":"214","author":"Tchaparian","year":"2016","journal-title":"J Infect Dis"},{"key":"2023020817103997800_ciac783-B24","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s12916-015-0456-7","article-title":"Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data","volume":"13","author":"WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK\/PD Study Group","year":"2015","journal-title":"BMC Med"},{"key":"2023020817103997800_ciac783-B25","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s12936-020-03287-5","article-title":"Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial","volume":"19","author":"Mhamilawa","year":"2020","journal-title":"Malar J"},{"key":"2023020817103997800_ciac783-B26","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01140-19","article-title":"A randomized controlled trial of three- versus five-day artemether-lumefantrine regimens for treatment of uncomplicated Plasmodium falciparum malaria in pregnancy in Africa","volume":"64","author":"Onyamboko","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"2023020817103997800_ciac783-B27","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1365-3156.2006.01785.x","article-title":"Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria","volume":"12","author":"Ashley","year":"2007","journal-title":"Trop Med Int Health"},{"key":"2023020817103997800_ciac783-B28","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2165\/00003088-199937020-00002","article-title":"Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine","volume":"37","author":"White","year":"1999","journal-title":"Clin Pharmacokinet"},{"key":"2023020817103997800_ciac783-B29","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S1473-3099(19)30535-3","article-title":"Suboptimal dosing triggers artemisinin partner drug resistance","volume":"19","author":"Wang","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"2023020817103997800_ciac783-B30","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1056\/NEJMp1901233","article-title":"A temporizing solution to \u201cartemisinin resistance\u201d","volume":"380","author":"Wang","year":"2019","journal-title":"N Engl J Med"},{"key":"2023020817103997800_ciac783-B31","doi-asserted-by":"crossref","first-page":"e77634","DOI":"10.7554\/eLife.77634","article-title":"The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum","volume":"11","author":"Masserey","year":"2022","journal-title":"Elife"},{"key":"2023020817103997800_ciac783-B32","article-title":"Strong correlation of lumefantrine concentrations in capillary and venous plasma from malaria patients","volume":"13","author":"Huang","year":"2018","journal-title":"PLoS One"},{"key":"2023020817103997800_ciac783-B33","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1186\/s12936-018-2404-4","article-title":"Effectiveness and safety of 3 and 5 day courses of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar","volume":"17","author":"Tun","year":"2018","journal-title":"Malar J"},{"key":"2023020817103997800_ciac783-B34","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1128\/AAC.44.3.697-704.2000","article-title":"Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria","volume":"44","author":"Ezzet","year":"2000","journal-title":"Antimicrob Agents Chemother"},{"key":"2023020817103997800_ciac783-B35","doi-asserted-by":"crossref","first-page":"ofw217","DOI":"10.1093\/ofid\/ofw217","article-title":"Parasite clearance and artemether pharmacokinetics parameters over the course of artemether-lumefantrine treatment for malaria in human immunodeficiency virus (HIV)-infected and HIV-uninfected Ugandan children","volume":"3","author":"Kajubi","year":"2016","journal-title":"Open Forum Infect Dis"},{"key":"2023020817103997800_ciac783-B36","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0924-8579(99)00063-1","article-title":"Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria","volume":"12","author":"van Agtmael","year":"1999","journal-title":"Int J Antimicrob Agents"},{"key":"2023020817103997800_ciac783-B37","article-title":"Population pharmacokinetics of artemether, dihydroartemisinin, and lumefantrine in Rwandese pregnant women treated for uncomplicated plasmodium falciparum malaria","volume":"62","author":"Das","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2023020817103997800_ciac783-B38","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.xphs.2020.09.023","article-title":"Auto-induction of intestinal first-pass effect related time-dependent pharmacokinetics of artemisinin rather than dihydroartemisinin","volume":"110","author":"Chai","year":"2021","journal-title":"J Pharm Sci"},{"key":"2023020817103997800_ciac783-B39","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/bdd.607","article-title":"Pharmacokinetics of dihydroartemisinin in artekin tablets for single and repeated dosing in Chinese healthy volunteers","volume":"29","author":"Hong","year":"2008","journal-title":"Biopharm Drug Dispos"},{"key":"2023020817103997800_ciac783-B40","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1128\/AAC.01717-08","article-title":"Pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam","volume":"53","author":"Nguyen","year":"2009","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciac783\/46564604\/ciac783.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/443\/49125750\/ciac783.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/76\/3\/443\/49125750\/ciac783.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T12:53:22Z","timestamp":1675860802000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/76\/3\/443\/6708265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,20]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,9,20]]},"published-print":{"date-parts":[[2023,2,8]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciac783","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,9,20]]}}}