{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:37:35Z","timestamp":1792237055822,"version":"4.4.0"},"reference-count":31,"publisher":"S. Karger AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2019,1,1]],"date-time":"2019-01-01T00:00:00Z","timestamp":1546300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neonatology"],"published-print":{"date-parts":[[2019]]},"abstract":"<jats:p>Background: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and\/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. Objectives: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. Methods: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and\/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2\u20135 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. Results: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9\u20132.9, p &lt; 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. Conclusions: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg\/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.<\/jats:p>","DOI":"10.1159\/000499330","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T17:00:33Z","timestamp":1561741233000},"page":"154-162","source":"Crossref","is-referenced-by-count":37,"title":["Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia"],"prefix":"10.1159","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-5236","authenticated-orcid":false,"given":"Laurent\u00a0M.A.","family":"Favi\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-1637","authenticated-orcid":false,"given":"Floris","family":"Groenendaal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel\u00a0P.H.","family":"van\u00a0den\u00a0Broek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carin\u00a0M.A.","family":"Rademaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo\u00a0R.","family":"de\u00a0Haan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrica\u00a0L.M.","family":"van\u00a0Straaten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter\u00a0H.","family":"Dijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno","family":"van\u00a0Heijst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5219-5696","authenticated-orcid":false,"given":"Sinno\u00a0H.P.","family":"Simons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0765-929X","authenticated-orcid":false,"given":"Koen\u00a0P.","family":"Dijkman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Rijken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge\u00a0A.","family":"Zonnenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6581-7009","authenticated-orcid":false,"given":"Filip","family":"Cools","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Zecic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna\u00a0H.","family":"van\u00a0der\u00a0Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie\u00a0H.G.M.","family":"Nuytemans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"van\u00a0Bel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toine\u00a0C.G.","family":"Egberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin\u00a0D.R.","family":"Huitema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on\u00a0behalf\u00a0of\u00a0the\u00a0PharmaCool\u00a0study\u00a0group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2019,6,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0900854"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1159\/000348823"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2017.07.008"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-012-0004-y"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00331-8"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1159\/000368180"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1109\/MINES.2012.126"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1080\/08035250410028057"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91209-6"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.027029"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra035092"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1284"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2011.07.015"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.55.4.506"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.59.7.1119"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.2165\/11319360-000000000-00000"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000281517.97507.6E"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2010.146"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-12-45"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-016-9487-8"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