{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:23:26Z","timestamp":1773422606765,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011392","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000}}],"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:00:00Z","timestamp":1688947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006483","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>The parasitic filariae responsible for onchocerciasis and lymphatic filariasis are host to an endosymbiotic bacterium, <jats:italic>Wolbachia<\/jats:italic>, which is essential to the fertility and development of the parasites. We performed a Phase-I pharmacokinetic, safety and food-effect study on single and multiple ascending doses of flubentylosin (ABBV-4083), a macrolide antibacterial with activity against <jats:italic>Wolbachia<\/jats:italic>, intended to sterilize and eliminate the parasites.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Seventy-eight healthy adults were exposed to flubentylosin; 36 were exposed to single ascending 40, 100, 200, 400 or 1000 mg doses; 12 received 1000 mg in the food-effect part; and 30 received multiple ascending daily doses of 100 mg for 7 days, 200 mg for 7 or 14 days, or 400 mg for 7 or 14 days. Twenty-two subjects received placebo.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Maximum concentrations (C<jats:sub>max<\/jats:sub>) of flubentylosin were reached after 1\u20132 hours, with a half-life &lt; 4 hours at doses \u2264 400 mg. C<jats:sub>max<\/jats:sub> and AUC increased in a more than dose-proportional manner, with similar exposure after multiple dose administration. The most frequently reported adverse events were nausea (8\/78, 10%) and headache (6\/78, 8%).<\/jats:p>\n<jats:p>Two subjects given a single dose of flubentylosin 1000 mg in the food-effect part experienced reversible asymptomatic ALT and AST elevations at Grade 2 or Grade 4, with no elevation in bilirubin, deemed related to study drug. The effect of food on exposure parameters was minimal. No treatment-related serious adverse events were reported.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>Flubentylosin 400 mg for 14 days was the maximum tolerated dose in this first-in-human, Phase-I study in healthy adults. Based on preclinical pharmacokinetic\/pharmacodynamic modeling, flubentylosin 400 mg once daily for 7 or 14 days is expected to be an effective dose. A Phase-II, proof-of-concept study with flubentylosin using these regimens is currently ongoing in patients with onchocerciasis in Africa.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0011392","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T17:59:34Z","timestamp":1689011974000},"page":"e0011392","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4455-5780","authenticated-orcid":true,"given":"Negar","family":"Alami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nisha V.","family":"Kwatra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Snodgrass","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariel R.","family":"Porcalla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheri E.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loretta","family":"Gallenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melina","family":"Neenan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kennan C.","family":"Marsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale J.","family":"Kempf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"key":"pntd.0011392.ref001","first-page":"392","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the Global Burden of Disease Study","volume":"10159","author":"SL James","year":"2017","journal-title":"Lancet"},{"issue":"5561","key":"pntd.0011392.ref002","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1126\/science.1068732","article-title":"The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness","volume":"295","author":"Av Saint Andr\u00e9","year":"2002","journal-title":"Science"},{"key":"pntd.0011392.ref003","volume-title":"Hunter\u2019s Tropical Medicine and Emerging Infectious Diseases","author":"AJ Magill","year":"2012","edition":"9"},{"key":"pntd.0011392.ref004","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1186\/1756-3305-7-363","article-title":"Multidimensional complexities of filariasis control in an era of large-scale mass drug administration programmes: A can of worms.","volume":"7","author":"DH Molyneux","year":"2014","journal-title":"Parasit. 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Modeling the impact of increased ivermectin treatment frequency and complementary vector control","volume":"66","author":"S Verver","year":"2018","journal-title":"Clin Infect Dis"},{"issue":"8","key":"pntd.0011392.ref014","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1093\/cid\/ciu1152","article-title":"Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness","volume":"60","author":"M Walker","year":"2015","journal-title":"Clin Infect Dis"},{"issue":"12","key":"pntd.0011392.ref015","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.pt.2021.06.004","article-title":"Anti-Wolbachia drugs for filariasis","volume":"37","author":"KL Johnston","year":"2021","journal-title":"Trends Parasitol"},{"issue":"2","key":"pntd.0011392.ref016","doi-asserted-by":"crossref","first-page":"e0007159","DOI":"10.1371\/journal.pntd.0007159","article-title":"Discovery of ABBV-4083, a novel analog of Tylosin-A that has potent anti-Wolbachia and anti-filarial activity.","volume":"13","author":"TW von Geldern","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"issue":"483","key":"pntd.0011392.ref017","doi-asserted-by":"crossref","first-page":"eaau2086","DOI":"10.1126\/scitranslmed.aau2086","article-title":"Preclinical development of an oral anti-Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis","volume":"11","author":"MJ Taylor","year":"2019","journal-title":"Sci Transl Med"},{"issue":"1","key":"pntd.0011392.ref018","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/bcpt.12550","article-title":"Systematic Review and Meta-Analysis: Macrolides- and Amoxicillin\/Clavulanate-induced Acute Liver Injury","volume":"119","author":"P Ferrer","year":"2016","journal-title":"Basic Clin Pharmacol Toxicol"},{"issue":"3","key":"pntd.0011392.ref019","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s11095-019-2582-y","article-title":"Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury Using Quantitative Systems Toxicology Modeling","volume":"36","author":"JL Woodhead","year":"2019","journal-title":"Pharm Res"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0011392","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011392","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T17:42:32Z","timestamp":1690306952000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011392"}},"subtitle":[],"editor":[{"given":"Cinzia","family":"Cantacessi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,7,10]]},"references-count":19,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011392","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0011392","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,10]]}}}