{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T12:11:02Z","timestamp":1776773462223,"version":"3.51.2"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T00:00:00Z","timestamp":1650844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Adult Clinical Trial Group"},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["AI068634"],"award-info":[{"award-number":["AI068634"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["AI068636"],"award-info":[{"award-number":["AI068636"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["AI106701"],"award-info":[{"award-number":["AI106701"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AI068634"],"award-info":[{"award-number":["AI068634"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AI068636"],"award-info":[{"award-number":["AI068636"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AI106701"],"award-info":[{"award-number":["AI106701"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["AI068632"],"award-info":[{"award-number":["AI068632"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD069175"],"award-info":[{"award-number":["R01HD069175"]}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council"},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15\u201325\u2005mg\/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3\u201312.6)\u2005years and 9.6 (3.9\u201334.5)\u2005kg, respectively. Children with HIV (HIV+; n\u200a=\u200a103) received ART (lopinavir\/ritonavir in 92%).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2\u2005months after birth and 99% by 3\u2005years. Typical steady-state apparent clearance in a 10\u2005kg child was 15.9\u2005L\/h. In HIV+ children on lopinavir\/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax\u200a=\u200a0.882 (0.669\u20131.28) versus 1.66 (1.21\u20132.15)\u2005mg\/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16\u2005years or older.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>To obtain exposure within the 2\u20136\u2005mg\/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir\/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac127","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T11:13:13Z","timestamp":1649934793000},"page":"1949-1959","source":"Crossref","is-referenced-by-count":9,"title":["Population pharmacokinetics of ethambutol in African children: a pooled analysis"],"prefix":"10.1093","volume":"77","author":[{"given":"Tjokosela","family":"Tikiso","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"McIlleron","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"},{"name":"Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-8749","authenticated-orcid":false,"given":"Mahmoud Tareq","family":"Abdelwahab","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrie","family":"Bekker","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anneke","family":"Hesseling","sequence":"additional","affiliation":[{"name":"Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chishala","family":"Chabala","sequence":"additional","affiliation":[{"name":"University of Zambia, School of Medicine and Children\u2019s Hospital, University Teaching Hospitals , Lusaka , Zambia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geraint","family":"Davies","sequence":"additional","affiliation":[{"name":"Malawi-Liverpool-Wellcome Research Unit , Blantyre , Malawi"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather J","family":"Zar","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Red Cross War Memorial Children\u2019s Hospital , Cape Town , South Africa"},{"name":"SA-MRC Unit on Child & Adolescent Health, University of Cape Town , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Rabie","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health and Family Centre for Research with Ubuntu (FAM-CRU), Stellenbosch University , Cape Town , South Africa"},{"name":"Tygerberg Children\u2019s Hospital , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Andrieux-Meyer","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative , Geneva , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice","family":"Lee","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases Initiative , Geneva , Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9070-8699","authenticated-orcid":false,"given":"Lubbe","family":"Wiesner","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark F","family":"Cotton","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health and Family Centre for Research with Ubuntu (FAM-CRU), Stellenbosch University , Cape Town , South Africa"},{"name":"Tygerberg Children\u2019s Hospital , Cape Town , South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7494-079X","authenticated-orcid":false,"given":"Paolo","family":"Denti","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , 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rifampin, isoniazid, pyrazinamide, and ethambutol in infants dosed according to revised WHO-recommended treatment guidelines","volume":"60","author":"Bekker","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"2022122116341901400_dkac127-B4","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00641-18","article-title":"Protein binding of first-line antituberculosis drugs","volume":"62","author":"Alghamdi","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2022122116341901400_dkac127-B5","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":"2022122116341901400_dkac127-B6","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1006\/phrs.1999.0526","article-title":"Effect of rifabutin on ethambutol pharmacokinetics in healthy 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