{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:06:17Z","timestamp":1779782777651,"version":"3.53.1"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000855","name":"University of Birmingham","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C49739\/A17456"],"award-info":[{"award-number":["C49739\/A17456"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CTRQQR\u20102021\/100003"],"award-info":[{"award-number":["CTRQQR\u20102021\/100003"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Information on mitoxantrone pharmacokinetics in children is lacking and reduced dosing regimens applied to infants are supported by limited scientific rationale. The current study characterized mitoxantrone pharmacokinetics in a childhood acute myeloid leukaemia patient population and provides a data\u2010informed assessment of dosing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A total of 282 plasma samples from 44 patients aged 0.9\u201317\u2009years, receiving intravenous mitoxantrone at doses of 12\u2009mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      \/day or 0.4\u2009mg\/kg\/day (patients &lt;12\u2009months, \u226410\u2009kg or &lt;0.5\u2009m\n                      <jats:sup>2<\/jats:sup>\n                      ), were analysed, and a population pharmacokinetic model was developed. Individual clearance (CL) values were used to calculate mitoxantrone area under the plasma concentration\u2010time curve (AUC) for each patient. Relationships among dosing regimen, pharmacokinetics and toxicity were assessed. Simulation of 1000 virtual patients, sampled from real covariate combinations, was used to investigate standardized patient dosing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A two\u2010compartment model with fixed allometric scaling best described the data, with a final population estimated CL of 39.1\u2009L\/h (residual standard error 9.6%) observed for a patient weighing 27.5\u2009kg. Infants receiving mg\/kg dosing exhibited lower AUC values (192\u2009\u00b1\u200975\u2009\u03bcg\u00b7h\/L) than the mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      group (317\u2009\u00b1\u2009184\u2009\u03bcg\u00b7h\/L). Simulations showed that a standardized 12\u2009mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      \/day dosing regimen would likely result in comparable AUCs across all ages. No correlation was observed between mitoxantrone AUC and incidence of severe toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade 3\/4) in this cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides novel insights into the pharmacokinetics of mitoxantrone in children. Infant patients receiving body weight\u2010based dosing regimens may be at risk of suboptimal drug exposure, and many of these patients may tolerate higher mitoxantrone doses in line with older children. This trial was registered with the EU Clinical Trials Register (EudraCT number 2014\u2010005066\u201030).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70436","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:01:19Z","timestamp":1768456879000},"page":"1760-1770","source":"Crossref","is-referenced-by-count":0,"title":["Population pharmacokinetics and dose\u2013response relationships of mitoxantrone in children with acute myeloid leukaemia"],"prefix":"10.1002","volume":"92","author":[{"given":"Andrew M.","family":"Brandon","sequence":"first","affiliation":[{"name":"Centre For Cancer, Translational And Clinical Research Institute Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinke","family":"Huisman\u2010Siebinga","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmacology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby","family":"Barnett","sequence":"additional","affiliation":[{"name":"Centre For Cancer, Translational And Clinical Research Institute Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Wetherell","sequence":"additional","affiliation":[{"name":"Cancer Research UK Clinical Trials Unit, School of Medical Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Kearns","sequence":"additional","affiliation":[{"name":"Cancer Research UK Clinical Trials Unit, School of Medical Sciences University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Gibson","sequence":"additional","affiliation":[{"name":"Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Heaney","sequence":"additional","affiliation":[{"name":"Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Smith","sequence":"additional","affiliation":[{"name":"Our Lady's Hospital for Sick Children  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Baruchel","sequence":"additional","affiliation":[{"name":"Assistance Publique \u2013 H\u00f4pitaux de Paris H\u00f4pital Robert Debr\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Petit","sequence":"additional","affiliation":[{"name":"Assistance Publique \u2013 H\u00f4pitaux de Paris H\u00f4pital Trousseau  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Moore","sequence":"additional","affiliation":[{"name":"Queensland Children's Hospital  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-6895","authenticated-orcid":false,"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D. 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