{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T22:33:54Z","timestamp":1788561234043,"version":"build-2803163510"},"reference-count":78,"publisher":"European Respiratory Society (ERS)","issue":"3","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014538","name":"Lembaga Pengelola Dana Pendidikan","doi-asserted-by":"publisher","award":["201711220412046"],"award-info":[{"award-number":["201711220412046"]}],"id":[{"id":"10.13039\/501100014538","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2022,10,10]]},"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We systematically searched MEDLINE, Embase and Web of Science (1990\u20132021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total\/extrapolated area under the plasma concentration\u2013time curve from 0 to 24\u2005h post-dose (AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      ) and peak plasma concentration (\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      and\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      were assessed with linear mixed-effects models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      were summarised for isoniazid (18.7 (95% CI 15.5\u201322.6)\u2005h\u00b7mg\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ), rifampicin (34.4 (95% CI 29.4\u201340.3)\u2005h\u00b7mg\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ), pyrazinamide (375.0 (95% CI 339.9\u2013413.7)\u2005h\u00b7mg\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) and ethambutol (8.0 (95% CI 6.4\u201310.0)\u2005h\u00b7mg\u00b7L\n                      <jats:sup>\u22121<\/jats:sup>\n                      ). Our multivariate models indicated that younger age (especially &lt;2\u2005years) and HIV-positive status were associated with lower AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      for isoniazid and pyrazinamide.\n                      <jats:italic>N<\/jats:italic>\n                      -acetyltransferase 2 rapid acetylators had lower isoniazid AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      and slow acetylators had higher isoniazid AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      than intermediate acetylators. Determinants of\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      were generally similar to those for AUC\n                      <jats:sub>0\u201324<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.01596-2022","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T12:00:28Z","timestamp":1667476828000},"page":"2201596","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":34,"title":["Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis"],"prefix":"10.1183","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0084-9018","authenticated-orcid":false,"given":"Fajri","family":"Gafar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roeland E.","family":"Wasmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"McIlleron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob E.","family":"Aarnoutse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5755-4133","authenticated-orcid":false,"given":"H. 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