{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:43:46Z","timestamp":1791434626668,"version":"4.3.3"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,3,26]],"date-time":"2014-03-26T00:00:00Z","timestamp":1395792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Anesthesia"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid na\u00efve adults is 0.058\u00a0mg\u00b7l<jats:sup>\u22121<\/jats:sup>, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06\u00a0mg\u00b7l<jats:sup>\u22121<\/jats:sup>. The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2\u2010ethylidine\u20101,5\u2010dimethyl\u20103,3\u2010diphenylpyrrolidine (<jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content>) and 2\u2010ethyl\u20105\u2010methyl\u20103,3\u2010diphenylpyrroline (<jats:styled-content style=\"fixed-case\">EMDP<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from four studies (age 33\u2010week <jats:styled-content style=\"fixed-case\">PMA<\/jats:styled-content>\u201015\u00a0years) were pooled (<jats:italic>n<\/jats:italic>\u00a0=\u00a056) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70\u2010kg person using an allometric model approach. Investigation was made of the racemate and metabolite (<jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">EMDP<\/jats:styled-content>) dispositions. In addition, neonatal data (<jats:italic>n<\/jats:italic>\u00a0=\u00a07) allowed further study of R\u2010 and S\u2010enantiomer pharmacokinetics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A three\u2010compartment linear disposition model best described the observed time\u2013concentration profiles with additional compartments for metabolites. Population parameter estimates (between\u2010subject variability) were central volume (V1) 21.5 (29%)\u00a0l\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>, peripheral volumes of distribution V2 75.1 (23%)\u00a0l\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup> and V3 484 (8%)\u00a0l\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>, clearance (<jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>) 9.45 (11%)l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>, and intercompartment clearances Q2 325 (21%)\u00a0l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup> and Q3 136 (14%)\u00a0l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>. <jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content> formation clearance was 9.1 (11%)\u00a0l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>, formation clearance of <jats:styled-content style=\"fixed-case\">EMDP<\/jats:styled-content> from <jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content> 7.4 (63%)l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup>, elimination clearance of <jats:styled-content style=\"fixed-case\">EDDP<\/jats:styled-content> was 40.9 (26%)\u00a0l\u00b7h<jats:sup>\u22121<\/jats:sup>\u00b770\u00a0kg<jats:sup>\u22121<\/jats:sup> and the rate constant for intermediate compartments 2.17 (43%)\u00a0h<jats:sup>\u22121<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup> per 8\u00a0h in neonates achieves a target concentration of 0.06\u00a0mg\u00b7l<jats:sup>\u22121<\/jats:sup> within 36\u00a0h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pan.12385","type":"journal-article","created":{"date-parts":[[2014,3,26]],"date-time":"2014-03-26T06:28:45Z","timestamp":1395815325000},"page":"591-601","source":"Crossref","is-referenced-by-count":78,"title":["The pharmacokinetics of methadone and its metabolites in neonates, infants, and children"],"prefix":"10.1111","volume":"24","author":[{"given":"Robert M.","family":"Ward","sequence":"first","affiliation":[{"name":"Department of Neonatology &amp; Pediatric Clinical Pharmacology University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Drover","sequence":"additional","affiliation":[{"name":"Department of Anesthesia Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory B.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Pediatrics Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Stemland","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of Virginia Charlottesville VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Utah College of Pharmacy Salt Lake City UT USA"},{"name":"Department of Anesthesiology University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Tristani\u2010Firouzi","sequence":"additional","affiliation":[{"name":"Divison of Pediatric Cardiology University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph A.","family":"Lugo","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy University of Utah College of Pharmacy Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Satterfield","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics University of Utah College of Pharmacy Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology University of Auckland Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,3,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318238fec5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(76)81074-8"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1754.1991.tb00360.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-006-9018-0"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/pan.12021"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2008.08.021"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3182512b26"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085689"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.05.003"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199630050-00001"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9592.2002.00616.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.48.113006.094708"},{"key":"e_1_2_8_14_1","first-page":"iv","article-title":"The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves","volume":"14","author":"Hill AV","year":"1910","journal-title":"J Ph\\ol"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1214\/aos\/1176344552"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-007-9081-1"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100241"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2012.05.079"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.054841"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2004.02079.x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2004.02116.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.03.003"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951102001087"},{"key":"e_1_2_8_24_1","unstructured":"FDA.Guidance for Industry. 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