{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:38:08Z","timestamp":1790746688692,"version":"4.1.0"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005790","name":"Thammasat University","doi-asserted-by":"publisher","award":["Postdoctoral Fellowship"],"award-info":[{"award-number":["Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/501100005790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005790","name":"Thammasat University","doi-asserted-by":"publisher","award":["1\/2556, dated 12 October 2013"],"award-info":[{"award-number":["1\/2556, dated 12 October 2013"]}],"id":[{"id":"10.13039\/501100005790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","award":["No 45\/2561"],"award-info":[{"award-number":["No 45\/2561"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","award":["NRCT 820\/2563"],"award-info":[{"award-number":["NRCT 820\/2563"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Declining in susceptibility of <jats:italic>Plasmodium falciparum<\/jats:italic> to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK\/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> malaria.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Data collected during 2008\u20132009 from 124 patients with uncomplicated <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients\u2019 adherence and parasite biomass.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>The developed PK\/PD models well described with clinically observed data. For mefloquine-resistant <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic>, a three-day standard regimen of artesunate-mefloquine is suitable (&gt;50% efficacy) only when the level of parasite sensitivity was &lt; 1.5-fold of the cut-off level (IC<jats:sub>50<\/jats:sub> &lt; 36 nM). For mefloquine-sensitive parasite with IC<jats:sub>50<\/jats:sub> &lt; 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC<jats:sub>50<\/jats:sub> of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C<jats:sub>336h<\/jats:sub> (&gt;408 ng.mL<jats:sup>-1<\/jats:sup>) or C<jats:sub>max<\/jats:sub>\/IC<jats:sub>50<\/jats:sub> (&gt;130.1 g.m\/M), and C<jats:sub>max<\/jats:sub>\/IC<jats:sub>50<\/jats:sub> (&gt;381.2 g.m\/M), respectively.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC<jats:sub>50<\/jats:sub> of <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC<jats:sub>50<\/jats:sub> is lower than 23.19 nM.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0282099","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T18:33:47Z","timestamp":1677177227000},"page":"e0282099","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Prediction of improved antimalarial chemotherapy of artesunate-mefloquine in combination with mefloquine sensitive and resistant Plasmodium falciparum malaria"],"prefix":"10.1371","volume":"18","author":[{"given":"Teerachat","family":"Saeheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-0897","authenticated-orcid":true,"given":"Kesara","family":"Na-Bangchang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"pone.0282099.ref001","volume-title":"World malaria report 2020: 20 years of global progress and challenges","author":"World Health Organization","year":"2021"},{"issue":"11","key":"pone.0282099.ref002","first-page":"626","article-title":"Efficacy and safety of artesunate-mefloquine therapy for treating uncomplicated Plasmodium falciparum malaria: systematic review and meta-analysis","volume":"110","author":"HM Peixoto","year":"2016","journal-title":"Trans R SoC Trop Med Hyg"},{"key":"pone.0282099.ref003","first-page":"46","article-title":"A randomized trial of artemeter-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand","volume":"4","author":"R Hutagalung","year":"2005","journal-title":"Mar J"},{"key":"pone.0282099.ref004","doi-asserted-by":"crossref","first-page":"246","DOI":"10.4269\/ajtmh.2001.64.247","article-title":"A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug -resistant Plasmodium falciparum malaria in Thailand","volume":"64","author":"G Lefevre","year":"2001","journal-title":"Am J Trop Med Hyg"},{"key":"pone.0282099.ref005","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1086\/424512","article-title":"Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine in the treatment of uncomplicated falciparum malaria in Lao People\u2019s Democratic Republic","volume":"39","author":"M Mayxay","year":"2004","journal-title":"Clin Infect Dis"},{"key":"pone.0282099.ref006","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S1473-3099(10)70187-0","article-title":"Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated malaria: An open-label randomized trial","volume":"10","author":"F Smithuis","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"pone.0282099.ref007","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1111\/j.1365-3156.2004.01320.x","article-title":"Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People\u2019s Democratic Republic","volume":"9","author":"JM Stohrer","year":"2004","journal-title":"Trop Med Int Health"},{"key":"pone.0282099.ref008","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1086\/432011","article-title":"A randomized, controlled study of a simple, one-daily regimen of dihydriartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria","volume":"41","author":"EA Ashley","year":"2005","journal-title":"Clin Infect Dis"},{"key":"pone.0282099.ref009","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1365-3156.2006.01786.x","article-title":"A randomized open study to assess the efficacy and tolerability of dihydriartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia","volume":"12","author":"B Janssens","year":"2007","journal-title":"Trop Med Int Health"},{"key":"pone.0282099.ref010","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1111\/j.1365-3156.2006.01671.x","article-title":"An open, randomized comparison of artesunate plus mefloquine vs. Dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Lao People\u2019s Democratic Republic (Laos)","volume":"11","author":"M Mayxay","year":"2006","journal-title":"Trop Med Int Health"},{"key":"pone.0282099.ref011","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1016\/S0140-6736(06)68931-9","article-title":"Efficacy and effectiveness of Dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomized comparison","volume":"367","author":"F Smithuis","year":"2006","journal-title":"Lancet"},{"key":"pone.0282099.ref012","first-page":"1085","article-title":"An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria","volume":"36","author":"N Tangpukdee","year":"2005","journal-title":"Southeast Asian J Trop Med Public Health"},{"key":"pone.0282099.ref013","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1475-2875-6-80","article-title":"Efficacy and tolerability to four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal","volume":"6","author":"B Faye","year":"2007","journal-title":"Malar J"},{"key":"pone.0282099.ref014","doi-asserted-by":"crossref","first-page":"140","DOI":"10.4269\/ajtmh.2010.09-0265","article-title":"A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children","volume":"82","author":"B Faye","year":"2010","journal-title":"Am J Trop Med Hyg"},{"key":"pone.0282099.ref015","doi-asserted-by":"crossref","first-page":"655","DOI":"10.4269\/ajtmh.2008.79.655","article-title":"A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali","volume":"79","author":"I Sagara","year":"2008","journal-title":"Am J Trop Med Hyg"},{"key":"pone.0282099.ref016","first-page":"416","article-title":"Efficacy and tolerability of a new formulation of artesunate-mefloquine for the treatment of uncomplicated malaria in adult in Senegal: open randomized trial","volume":"11","author":"RCK Tine","year":"2012","journal-title":"Mar J"},{"key":"pone.0282099.ref017","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.1365-3156.2010.02701.x","article-title":"Artesunate\/mefloquine paediatric formulation vs. artemether\/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua koute Cote d\u2019lvoire","volume":"16","author":"OA Toure","year":"2011","journal-title":"Trop Med Int Heal"},{"issue":"9","key":"pone.0282099.ref018","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1186\/1475-2875-9-273","article-title":"Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border","volume":"8","author":"K. Na-Bangchang","year":"2010","journal-title":"Mala J"},{"issue":"12","key":"pone.0282099.ref019","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.1128\/AAC.00287-13","article-title":"Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization","volume":"57","author":"NJ White","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"pone.0282099.ref020","doi-asserted-by":"crossref","first-page":"e1003151","DOI":"10.1371\/journal.pcbi.1003151","article-title":"Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs","volume":"9","author":"K Kay","year":"2013","journal-title":"PLoS Comput Biol"},{"issue":"5","key":"pone.0282099.ref021","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1208\/s12248-014-9647-y","article-title":"Making the most of clinical data: reviewing the role of pharmacokinetic-pharmacodynamic models of anti-malarial drugs","volume":"16","author":"JA Simpson","year":"2014","journal-title":"AAPS J"},{"issue":"4","key":"pone.0282099.ref022","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/cpt.2238","article-title":"Malaria PK\/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations","volume":"110","author":"E Hughes","year":"2021","journal-title":"Clin Pharmacol Ther"},{"key":"pone.0282099.ref023","doi-asserted-by":"crossref","first-page":"104065","DOI":"10.1016\/j.ebiom.2022.104065","article-title":"Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development","volume":"80","author":"AH Gaur","year":"2022","journal-title":"EBioMedicine"},{"issue":"37","key":"pone.0282099.ref024","article-title":"In vitro antimalarial drug susceptibility in Thai border areas from 1998\u20132003","volume":"4","author":"W. Chaijaroenkul","year":"2005","journal-title":"Mala J"},{"issue":"6","key":"pone.0282099.ref025","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.4269\/ajtmh.19-0094","article-title":"Beyond blood smears: Qualification of Plasmodium 18S rRNA as biomarker for controlled human malaria infections","volume":"100","author":"AM Seilie","year":"2019","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"pone.0282099.ref026","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12936-018-2278-5","article-title":"Population pharmacokinetic and pharmacodynamic properties of artesunate in patients with artemisinin sensitive and resistant infections in Southern Myanmar","volume":"17","author":"JPL Das","year":"2018","journal-title":"Mala J"},{"issue":"1","key":"pone.0282099.ref027","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pt.2020.09.011","article-title":"Triple Artemisinin-Based Combination Therapies for Malaria\u2014A New Paradigm?","volume":"37","author":"RW van der Pluijm","year":"2021","journal-title":"Trends Parasitol"},{"issue":"10233","key":"pone.0282099.ref028","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(20)30552-3","article-title":"Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial","volume":"395","author":"RW van der Pluijm","year":"2020","journal-title":"Lancet"},{"key":"pone.0282099.ref029","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/1475-2875-10-278","article-title":"The parasite clearance curve","volume":"10","author":"NJ White","year":"2011","journal-title":"Malar J"},{"key":"pone.0282099.ref030","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1475-2875-2-14","article-title":"The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro","volume":"2","author":"GS Dow","year":"2003","journal-title":"Malar J"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T18:34:09Z","timestamp":1677177249000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282099"}},"subtitle":[],"editor":[{"given":"Benedikt","family":"Ley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,2,23]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0282099","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,23]]}}}