{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:26:59Z","timestamp":1790000819089,"version":"4.0.1"},"reference-count":55,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["18E2H24N"],"award-info":[{"award-number":["18E2H24N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G0D0520N"],"award-info":[{"award-number":["G0D0520N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and purpose<\/jats:title>\n                    <jats:p>\n                      Therapeutic hypothermia (TH) decreases morbidity and mortality in neonates with perinatal asphyxia (PA) and moderate\u2010to\u2010severe hypoxic\u2013ischaemic encephalopathy. Midazolam is an antiepileptic and substrate of CYP3A4. Drug metabolism during PA\/TH remains partially characterized, and disentangling effects of PA and TH is difficult, making precision dosing challenging. The I\u2010PREDICT project aims to develop a framework for drug disposition in PA\/TH neonates, using physiologically based pharmacokinetic (PBPK) modelling. The predictive performance of the model was explored for midazolam and its active metabolites, 1\u2032\u2010hydroxymidazolam and 1\u2032\u2010hydroxymidazolam\u2010\n                      <jats:italic>O<\/jats:italic>\n                      \u2010glucuronide, in neonates with PA\/TH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>The model was established stepwise, starting with healthy adults, and extrapolated to paediatric (1\u00a0month\u201318\u2009years) and neonatal (0\u201327\u2009days, non\u2010asphyxiated) populations. Finally, PA\/TH\u2010related physiological and metabolic changes were incorporated. For each population, performance was verified using clinical data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>Model predictive performance for midazolam and 1\u2032\u2010hydroxymidazolam was acceptable in adults and children, with AFE and AAFE values ranging from 0.87 to 1.22 and 1.15 to 1.23, respectively. The neonatal PA\/TH PBPK model captured midazolam pharmacokinetics, with 71% of the observations within the 10th\u201390th percentiles and 46% within the 25th\u201375th percentiles of the prediction. Incorporating PA\/TH physiology improved the neonatal PA\/TH model by 6%\u201343% (within the 10th\u201390th percentiles), depending on the compound.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>\n                      This PA\/TH\u2010adjusted neonatal PBPK model may support future midazolam dose optimization through mechanistic understanding and provides a framework for other drugs in neonates with PA\/TH. Future knowledge on the impact of TH on protein binding and renal clearance of 1\u2032\u2010hydroxymidazolam\u2010\n                      <jats:italic>O<\/jats:italic>\n                      \u2010glucuronide would further improve the model.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70601","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T14:15:43Z","timestamp":1778681743000},"page":"3124-3139","source":"Crossref","is-referenced-by-count":1,"title":["Neonatal PBPK model of midazolam and its metabolites for perinatal asphyxia and therapeutic hypothermia"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4931-6562","authenticated-orcid":false,"given":"Karen","family":"Leys","sequence":"first","affiliation":[{"name":"Drug Delivery and Disposition Unit, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3120-3911","authenticated-orcid":false,"given":"Agustos","family":"Ozbey","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Development Unit Idorsia Pharmaceuticals  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-039X","authenticated-orcid":false,"given":"Miao\u2010Chan","family":"Huang","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition Unit, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-5867","authenticated-orcid":false,"given":"Julia","family":"Macente","sequence":"additional","affiliation":[{"name":"Drug Delivery and Disposition Unit, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-9458","authenticated-orcid":false,"given":"Marina\u2010Stefania","family":"Stroe","sequence":"additional","affiliation":[{"name":"Comparative Perinatal Development Group University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-3918","authenticated-orcid":false,"given":"Timo Robert","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Emma Children's Hospital Amsterdam University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-1637","authenticated-orcid":false,"given":"Floris","family":"Groenendaal","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Wilhelmina Children's Hospital University Medical Center Utrecht and Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-7067","authenticated-orcid":false,"given":"Evelyne","family":"Jacqz\u2010Aigrain","sequence":"additional","affiliation":[{"name":"Pharmacologie H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0502-0647","authenticated-orcid":false,"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Toxicology Radboud University Medical Center  Nijmegen the Netherlands"},{"name":"Department of Neonatal and Paediatric Intensive Care Erasmus MC Sophia Children's Hospital  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-5105","authenticated-orcid":false,"given":"Karel","family":"Allegaert","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Erasmus MC  Rotterdam the Netherlands"},{"name":"Department of Development and Regeneration KU Leuven  Leuven Belgium"},{"name":"Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences KU Leuven  Leuven Belgium"},{"name":"L\u2010C&amp;Y, KU Leuven Child &amp; 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