{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:02:31Z","timestamp":1792414951109,"version":"4.4.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPPGH 5342"],"award-info":[{"award-number":["OPPGH 5342"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Ivermectin (IVM) is a broad\u2013spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple\u2013drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub\u2013Saharan Africa. The drug shows high variability in drug exposure in previous pharmacokinetic studies. This study aims to build a population pharmacokinetic (PopPK) model to identify and quantify the possible sources of the variability of IVM exposure after a single\u2013oral dose in LF\u2013infected subjects and healthy individuals.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology \/ Principal findings<\/jats:title>\n<jats:p>In this analysis, 724 samples were collected from treatment\u2013na\u00efve <jats:italic>Wuchereria bancrofti<\/jats:italic>\u2013infected (<jats:italic>n<\/jats:italic> = 32) and uninfected (<jats:italic>n<\/jats:italic> = 24) adults living in C\u00f4te d\u2019Ivoire who had received one dose of IVM as a part of triple\u2013drug therapy. PopPK analysis was conducted using Phoenix NLME 8.3 software. The Monte Carlo simulation based on the final model was performed to simulate drug exposure among different dosing groups (200 \u03bcg\/kg, 18 mg, and 36 mg). A two\u2013compartment model with zero\u2013order dose input into the absorption compartment with a lag time function followed by first\u2013order absorption and linear elimination best described the IVM\u2019s pharmacokinetic (PK) parameters. The final model identifies that the PK parameters of IVM are not affected by LF infection. Sex was a significant covariate on the peripheral volume of distribution (Vp\/<jats:italic>F<\/jats:italic>, 53% lower in men than in women). IVM drug exposure shows linear pharmacokinetic behavior among the simulated dosing groups with similar drug exposure based on sex.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion\/Significance<\/jats:title>\n<jats:p>We have developed a PopPk model to describe and identify possible sources of the variability of IVM exposure. To our knowledge, this is the first PopPK study of IVM in patients with LF.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02845713?term=NCT02845713&amp;draw=2&amp;rank=1\" xlink:type=\"simple\">NCT02845713<\/jats:ext-link>; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03664063?term=NCT03664063&amp;draw=2&amp;rank=1\" xlink:type=\"simple\">NCT03664063<\/jats:ext-link><\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0011319","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T17:23:37Z","timestamp":1685640217000},"page":"e0011319","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis"],"prefix":"10.1371","volume":"17","author":[{"given":"Abdullah","family":"Alshehri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashpal S.","family":"Chhonker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veenu","family":"Bala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constant","family":"Edi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine M.","family":"Bjerum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Koudou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy N.","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriol","family":"Mitj\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4169-5027","authenticated-orcid":true,"given":"Daryl J.","family":"Murry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"issue":"2","key":"pntd.0011319.ref001","first-page":"135","article-title":"Lymphatic filariasis: diagnosis and pathogenesis. WHO expert committee on filariasis","volume":"71","year":"1993","journal-title":"Bull World Health Organ"},{"issue":"40","key":"pntd.0011319.ref002","first-page":"589","article-title":"Summary of global update on preventive chemotherapy implementation in 2016: crossing the billion.","volume":"92","year":"2017","journal-title":"Wkly Epidemiol Rec"},{"issue":"12","key":"pntd.0011319.ref003","doi-asserted-by":"crossref","first-page":"e3328","DOI":"10.1371\/journal.pntd.0003328","article-title":"Global programme to eliminate lymphatic filariasis: the processes underlying programme success.","volume":"8","author":"K Ichimori","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0011319.ref004","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.12688\/gatesopenres.13065.1","article-title":"The roadmap towards elimination of lymphatic filariasis by 2030: insights from quantitative and mathematical modelling","volume":"3","year":"2019","journal-title":"Gates Open Res"},{"issue":"4","key":"pntd.0011319.ref005","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S1473-3099(16)30467-4","article-title":"Effectiveness of a triple\u2013drug regimen for global elimination of lymphatic filariasis: a modelling study","volume":"17","author":"MA Irvine","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"5","key":"pntd.0011319.ref006","doi-asserted-by":"crossref","first-page":"e0007325","DOI":"10.1371\/journal.pntd.0007325","article-title":"Pharmacokinetics, safety, and efficacy of a single co\u2013administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in C\u00f4te d\u2019Ivoire.","volume":"13","author":"C Edi","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"issue":"19","key":"pntd.0011319.ref007","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJMoa1706854","article-title":"A Trial of a Triple\u2013Drug Treatment for Lymphatic Filariasis","volume":"379","author":"CL King","year":"2018","journal-title":"N Engl J Med"},{"issue":"8","key":"pntd.0011319.ref008","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/BF03261928","article-title":"Fundamentals of population pharmacokinetic modelling: modelling and software.","volume":"51","author":"TK Kiang","year":"2012","journal-title":"Clin Pharmacokinet."},{"issue":"6","key":"pntd.0011319.ref009","doi-asserted-by":"crossref","first-page":"210","DOI":"10.18773\/austprescr.2014.078","article-title":"Population pharmacokinetics: an overview","volume":"37","author":"B. Charles","year":"2014","journal-title":"Aust Prescr"},{"issue":"9","key":"pntd.0011319.ref010","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1038\/psp.2012.4","article-title":"Basic concepts in population modeling, simulation, and model\u2013based drug development","volume":"1","author":"DR Mould","year":"2012","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"10","key":"pntd.0011319.ref011","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1345\/aph.1D374","article-title":"Population pharmacokinetics I: background, concepts, and models","volume":"38","author":"EI Ette","year":"2004","journal-title":"Ann Pharmacother"},{"issue":"3","key":"pntd.0011319.ref012","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1111\/bcp.13840","article-title":"Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers","volume":"85","author":"U Duthaler","year":"2019","journal-title":"Br J Clin Pharmacol"},{"issue":"5","key":"pntd.0011319.ref013","doi-asserted-by":"crossref","first-page":"e236","DOI":"10.1371\/journal.pntd.0000236","article-title":"The effect of azithromycin on ivermectin pharmacokinetics\u2013\u2013a population pharmacokinetic model analysis.","volume":"2","author":"A El\u2013Tahtawy","year":"2008","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0011319.ref014","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1186\/s12936-017-1923-8","article-title":"Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles.","volume":"16","author":"KC Kobylinski","year":"2017","journal-title":"Malar J."},{"issue":"10\u201311","key":"pntd.0011319.ref015","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.addr.2011.05.019","article-title":"Intestinal lymphatic transport for drug delivery","volume":"63","author":"JA Y\u00e1\u00f1ez","year":"2011","journal-title":"Adv Drug Deliv Rev"},{"key":"pntd.0011319.ref016","volume-title":"Guideline: Alternative Mass Drug Administration Regimens to Eliminate Lymphatic Filariasis","year":"2017"},{"issue":"10","key":"pntd.0011319.ref017","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1177\/009127002237994","article-title":"Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects","volume":"42","author":"CA Guzzo","year":"2002","journal-title":"J Clin Pharmacol"},{"issue":"1","key":"pntd.0011319.ref018","doi-asserted-by":"crossref","first-page":"e0006020","DOI":"10.1371\/journal.pntd.0006020","article-title":"Safety and pharmacokinetic profile of fixed\u2013dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.","volume":"12","author":"J Mu\u00f1oz","year":"2018","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"pntd.0011319.ref019","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.jpba.2005.08.026","article-title":"Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies","volume":"40","author":"D Kitzman","year":"2006","journal-title":"J Pharm Biomed Anal"},{"key":"pntd.0011319.ref020","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jpba.2017.12.037","article-title":"LC\u2013MS\/MS method for simultaneous determination of diethylcarbamazine, albendazole and albendazole metabolites in human plasma: Application to a clinical pharmacokinetic study","volume":"151","author":"YS Chhonker","year":"2018","journal-title":"J Pharm Biomed Anal"},{"issue":"22","key":"pntd.0011319.ref021","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.4155\/bio-2018-0110","article-title":"A sensitive and selective LC\u2013MS\/MS method for quantitation of ivermectin in human, mouse and monkey plasma: clinical validation.","volume":"10","author":"YS Chhonker","year":"2018","journal-title":"Bioanalysis"},{"issue":"1","key":"pntd.0011319.ref022","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1208\/s12248-007-9000-9","article-title":"The pharmacokinetics and interactions of ivermectin in humans\u2013\u2013a mini\u2013review.","volume":"10","author":"A Gonz\u00e1lez Canga","year":"2008","journal-title":"Aaps j"},{"issue":"12","key":"pntd.0011319.ref023","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.1038\/psp.2014.51","article-title":"Introduction to population pharmacokinetic\/pharmacodynamic analysis with nonlinear mixed effects models.","volume":"3","author":"PH Graaf","year":"2014","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"4","key":"pntd.0011319.ref024","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1038\/psp.2013.14","article-title":"Basic concepts in population modeling, simulation, and model\u2013based drug development\u2013part 2: introduction to pharmacokinetic modeling methods.","volume":"2","author":"DR Mould","year":"2013","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"pntd.0011319.ref025","article-title":"Pharmacokinetic and safety study of co\u2013administration of albendazole, diethylcarbamazine, Ivermectin and azithromycin for the integrated treatment of Neglected Tropical Diseases","author":"LN John","year":"2020","journal-title":"Clin Infect Dis"},{"issue":"3","key":"pntd.0011319.ref026","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2165\/00003088-200948030-00001","article-title":"Sex differences in pharmacokinetics and pharmacodynamics.","volume":"48","author":"OP Soldin","year":"2009","journal-title":"Clin Pharmacokinet"},{"issue":"2","key":"pntd.0011319.ref027","first-page":"438","article-title":"The effect of food on the pharmacokinetics of oral ivermectin","volume":"75","author":"U Duthaler","year":"2020","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"pntd.0011319.ref028","first-page":"221","article-title":"Are population pharmacokinetic and\/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004","volume":"46","author":"K Brendel","year":"2007","journal-title":"Clin Pharmacokinet"},{"issue":"5","key":"pntd.0011319.ref029","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/micc.12031","article-title":"Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis","volume":"20","author":"S Chakraborty","year":"2013","journal-title":"Microcirculation"},{"issue":"1s","key":"pntd.0011319.ref030","doi-asserted-by":"crossref","first-page":"254s","DOI":"10.18433\/jpps30217","article-title":"Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development","volume":"21","author":"DR Brocks","year":"2018","journal-title":"J Pharm Pharm Sci"},{"issue":"5","key":"pntd.0011319.ref031","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1007\/s00204-021-03025-z","article-title":"Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects","volume":"95","author":"SP Rendic","year":"2021","journal-title":"Arch Toxicol"},{"issue":"1","key":"pntd.0011319.ref032","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/1471-2350-11-111","article-title":"Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?","volume":"11","author":"W Kudzi","year":"2010","journal-title":"BMC Medical Genetics"}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011319","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T17:24:04Z","timestamp":1685640244000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011319"}},"subtitle":[],"editor":[{"given":"Marc P.","family":"Hubner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011319","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,1]]}}}