{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:49:59Z","timestamp":1760233799929,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure\u2013response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of \u226460 ng\/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.<\/jats:p>","DOI":"10.3390\/children8030174","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T05:20:08Z","timestamp":1614230408000},"page":"174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-0657","authenticated-orcid":false,"given":"Samira","family":"Samiee-Zafarghandy","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Paediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"van Donge","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pharmacology and Pharmacometrics, University Children\u2019s Hospital Basel (UKBB), University of Basel, 4056 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-5105","authenticated-orcid":false,"given":"Karel","family":"Allegaert","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Erasmus MC, Postbus 2040, 3000 CA Rotterdam, The Netherlands"},{"name":"Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"},{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"van den Anker","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pharmacology and Pharmacometrics, University Children\u2019s Hospital Basel (UKBB), University of Basel, 4056 Basel, Switzerland"},{"name":"Division of Clinical Pharmacology, Children\u2019s National Health Hospital, Washington, DC 20010, USA"},{"name":"Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children\u2019s Hospital, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.15585\/mmwr.mm655051e1","article-title":"Increases in Drug and Opioid-Involved Overdose Deaths\u2014United States, 2010\u20132015","volume":"65","author":"Rudd","year":"2016","journal-title":"Mmwr. 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