{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:13:14Z","timestamp":1790903594375,"version":"4.1.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2019,7,5]],"date-time":"2019-07-05T00:00:00Z","timestamp":1562284800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000060","name":"the National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AI104441"],"award-info":[{"award-number":["R21AI104441"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23AI102639"],"award-info":[{"award-number":["K23AI102639"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To perform a population pharmacokinetic study of ethambutol in HIV\/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a prospective study of ethambutol pharmacokinetics among HIV\/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We studied 40 HIV\/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33\u2009days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400\u2009mg daily led to &gt;2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Low serum ethambutol concentrations were commonly observed among HIV\/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV\/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkz265","type":"journal-article","created":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T15:13:46Z","timestamp":1560179626000},"page":"2994-3002","source":"Crossref","is-referenced-by-count":12,"title":["Optimizing ethambutol dosing among HIV\/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study"],"prefix":"10.1093","volume":"74","author":[{"given":"Krina","family":"Mehta","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, University of Maryland, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruthi","family":"Ravimohan","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Lawrenceville, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jotam G","family":"Pasipanodya","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashikant","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chawangwa","family":"Modongo","sequence":"additional","affiliation":[{"name":"Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola M","family":"Zetola","sequence":"additional","affiliation":[{"name":"Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Weissman","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Ivaturi","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, University of Maryland, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tawanda","family":"Gumbo","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory P","family":"Bisson","sequence":"additional","affiliation":[{"name":"University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Vinnard","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, New Jersey Medical School, Newark, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,7,4]]},"reference":[{"key":"2019092005520298900_dkz265-B1","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1093\/cid\/ciw376","article-title":"Official American Thoracic Society\/Centers for Disease Control and Prevention\/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis","volume":"63","author":"Nahid","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B2","first-page":"796","article-title":"Role of individual drugs in the chemotherapy of tuberculosis","volume":"4","author":"Mitchison","year":"2000","journal-title":"Int J Tuberc Lung Dis"},{"key":"2019092005520298900_dkz265-B3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1128\/AAC.03931-14","article-title":"Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis","volume":"59","author":"Chigutsa","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B4","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S1473-3099(10)70139-0","article-title":"Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis","volume":"10","author":"Caminero","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"2019092005520298900_dkz265-B5","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1164\/rccm.201711-2333OC","article-title":"Drug penetration gradients associated with acquired drug resistance in tuberculosis patients","volume":"198","author":"Dheda","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2019092005520298900_dkz265-B6","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1111\/j.1749-6632.1966.tb45532.x","article-title":"The ocular toxicity of ethambutol and its relation to dose","volume":"135","author":"Leibold","year":"1966","journal-title":"Ann N Y Acad Sci"},{"key":"2019092005520298900_dkz265-B7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0954-6111(06)80294-5","article-title":"Ocular toxicity of ethambutol","volume":"85","author":"Harcombe","year":"1991","journal-title":"Respir Med"},{"key":"2019092005520298900_dkz265-B8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.7326\/0003-4819-127-4-199708150-00006","article-title":"Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection","volume":"127","author":"Sahai","year":"1997","journal-title":"Ann Intern Med"},{"key":"2019092005520298900_dkz265-B9","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1128\/AAC.00274-11","article-title":"Population pharmacokinetics of ethambutol in South African tuberculosis patients","volume":"55","author":"Jonsson","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B10","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1086\/498024","article-title":"The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis","volume":"41","author":"Perlman","year":"2005","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B11","doi-asserted-by":"crossref","first-page":"e0141002.","DOI":"10.1371\/journal.pone.0141002","article-title":"Pharmacokinetics of isoniazid, pyrazinamide, and ethambutol in newly diagnosed pulmonary TB patients in Tanzania","volume":"10","author":"Denti","year":"2015","journal-title":"PLoS One"},{"key":"2019092005520298900_dkz265-B12","doi-asserted-by":"crossref","first-page":"6175","DOI":"10.1128\/AAC.01193-15","article-title":"Pharmacokinetics of antituberculosis drugs in HIV-positive and HIV-negative adults in Malawi","volume":"59","author":"Van Oosterhout","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B13","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1128\/AAC.01355-09","article-title":"Ethambutol optimal clinical dose and susceptibility breakpoint identification by use of a novel pharmacokinetic-pharmacodynamic model of disseminated intracellular Mycobacterium avium","volume":"54","author":"Deshpande","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B14","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1086\/651377","article-title":"Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol","volume":"201","author":"Srivastava","year":"2010","journal-title":"J Infect Dis"},{"key":"2019092005520298900_dkz265-B15","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1086\/430377","article-title":"Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin- or rifabutin-based regimens in New York City, 1997-2000","volume":"41","author":"Li","year":"2005","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1086\/375220","article-title":"Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review","volume":"37","author":"Korenromp","year":"2003","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B17","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/bcp.13172","article-title":"Isoniazid clearance is impaired among human immunodeficiency virus\/tuberculosis patients with high levels of immune activation","volume":"83","author":"Vinnard","year":"2017","journal-title":"Br J Clin Pharmacol"},{"key":"2019092005520298900_dkz265-B18","doi-asserted-by":"crossref","first-page":"e0187624.","DOI":"10.1371\/journal.pone.0187624","article-title":"Pyrazinamide clearance is impaired among HIV\/tuberculosis patients with high levels of systemic immune activation","volume":"12","author":"Vinnard","year":"2017","journal-title":"PLoS One"},{"key":"2019092005520298900_dkz265-B19","doi-asserted-by":"crossref","first-page":"2020.","DOI":"10.1093\/jac\/dkx111","article-title":"Markers of gut dysfunction do not explain low rifampicin bioavailability in HIV-associated TB","volume":"72","author":"Vinnard","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"2019092005520298900_dkz265-B20","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1128\/AAC.47.9.2888-2891.2003","article-title":"Optimal sampling schedule design for populations of patients","volume":"47","author":"Tam","year":"2003","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B21","first-page":"904","article-title":"Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study","volume":"6","author":"Giorgi","year":"1993","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2019092005520298900_dkz265-B22","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1093\/infdis\/jiq118","article-title":"Plasma levels of soluble CD14 independently predict mortality in HIV infection","volume":"203","author":"Sandler","year":"2011","journal-title":"J Infect Dis"},{"key":"2019092005520298900_dkz265-B23","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1093\/infdis\/jiv089","article-title":"The interplay between host genetic variation, viral replication, and microbial translocation in untreated HIV-infected individuals","volume":"212","author":"Perkins","year":"2015","journal-title":"J Infect Dis"},{"key":"2019092005520298900_dkz265-B24","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1128\/AAC.05623-11","article-title":"Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people","volume":"56","author":"Hall","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B25","first-page":"S84","article-title":"Simulation from ODE-based population PK\/PD and systems pharmacology models in R with mrgsolve","volume":"W-23","author":"Baron","year":"2015","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2019092005520298900_dkz265-B26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1128\/AAC.00749-10","article-title":"An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future","volume":"55","author":"Pasipanodya","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B27","doi-asserted-by":"crossref","first-page":"e00924-17","DOI":"10.1128\/AAC.00924-17","article-title":"Ethambutol partitioning in tuberculous pulmonary lesions explains its clinical efficacy","volume":"61","author":"Zimmerman","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B28","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1128\/AAC.01474-09","article-title":"New susceptibility breakpoints for first-line antituberculosis drugs based on antimicrobial pharmacokinetic\/pharmacodynamic science and population pharmacokinetic variability","volume":"54","author":"Gumbo","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2019092005520298900_dkz265-B29","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s40265-014-0222-8","article-title":"Therapeutic drug monitoring in the treatment of tuberculosis: an update","volume":"74","author":"Alsultan","year":"2014","journal-title":"Drugs"},{"key":"2019092005520298900_dkz265-B30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1093\/jac\/dkp262","article-title":"Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis","volume":"64","author":"Sch\u00f6n","year":"2009","journal-title":"J Antimicrob Chemother"},{"key":"2019092005520298900_dkz265-B31"},{"key":"2019092005520298900_dkz265-B32","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/infdis\/jiu610","article-title":"Pharmacokinetic-pharmacodynamic and dose\u2013response relationships of antituberculosis drugs: recommendations and standards for industry and academia","volume":"211","author":"Gumbo","year":"2015","journal-title":"J Infect Dis"},{"key":"2019092005520298900_dkz265-B33","doi-asserted-by":"crossref","first-page":"S349","DOI":"10.1093\/cid\/ciy623","article-title":"Transformation morphisms and time-to-extinction analysis that map therapy duration from preclinical models to patients with tuberculosis: translating from apples to oranges","volume":"67","author":"Magombedze","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B34","doi-asserted-by":"crossref","first-page":"e152.","DOI":"10.1371\/journal.pmed.0050152","article-title":"Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies","volume":"5","author":"Jeon","year":"2008","journal-title":"PLoS Med"},{"key":"2019092005520298900_dkz265-B35","doi-asserted-by":"crossref","first-page":"447","DOI":"10.5588\/ijtld.11.0766","article-title":"Incidence of ethambutol-related visual impairment during treatment of active tuberculosis","volume":"17","author":"Ezer","year":"2013","journal-title":"Int J Tuberc Lung Dis"},{"key":"2019092005520298900_dkz265-B36","first-page":"1","article-title":"Ocular toxicity with ethambutol therapy: timely recaution","volume":"32","author":"Koul","year":"2015","journal-title":"Lung India"},{"key":"2019092005520298900_dkz265-B37","doi-asserted-by":"crossref","first-page":"S359","DOI":"10.1093\/cid\/ciy627","article-title":"Efficacy versus hepatotoxicity of high-dose rifampin, pyrazinamide, and moxifloxacin to shorten tuberculosis therapy duration: there is still fight in the old warriors yet!","volume":"67","author":"Srivastava","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2019092005520298900_dkz265-B38","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1128\/AAC.45.10.2891-2896.2001","article-title":"Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations","volume":"45","author":"Conte","year":"2001","journal-title":"Antimicrob Agents Chemother"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jac\/advance-article-pdf\/doi\/10.1093\/jac\/dkz265\/28905182\/dkz265.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jac\/article-pdf\/74\/10\/2994\/30039436\/dkz265.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T19:43:55Z","timestamp":1569267835000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/74\/10\/2994\/5528382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,4]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,7,4]]},"published-print":{"date-parts":[[2019,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkz265","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10]]},"published":{"date-parts":[[2019,7,4]]}}}