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However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2\u2010center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82\u20135.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine\u20103\u2010glucuronide and morphine\u20106\u2010gluronide) were measured via a validated dried blood spot liquid chromatography\u2013tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed\u2010effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5\u2010kg neonate, morphine clearance was 0.77 L\/h (CV, 48%), and the steady\u2010state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full\u2010term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng\/mL. An optimized morphine loading dose of 50 \u03bcg\/kg followed by a continuous infusion of 5 \u03bcg\/kg\/h was predicted across birthweights.<\/jats:p>","DOI":"10.1002\/jcph.775","type":"journal-article","created":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T10:23:28Z","timestamp":1464258208000},"page":"64-76","source":"Crossref","is-referenced-by-count":52,"title":["Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia"],"prefix":"10.1002","volume":"57","author":[{"given":"Adam","family":"Frymoyer","sequence":"first","affiliation":[{"name":"Department of Pediatrics Stanford University  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia L.","family":"Bonifacio","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Drover","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney J.","family":"Wustoff","sequence":"additional","affiliation":[{"name":"Division of Child Neurology Stanford University  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisa P.","family":"Van Meurs","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University  Palo Alto CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,6,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0900854"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17946-X"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2007.00361.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2002.023093"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767050701287459"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2010.146"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.1263"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2013.59"},{"key":"e_1_2_9_10_1","volume-title":"Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act","author":"IOM (Institute of Medicine)","year":"2012"},{"key":"e_1_2_9_11_1","unstructured":"Codeine and Morphine Pathway Pharmacokinetics [PharmGKB] [Internet].http:\/\/www.pharmgkb.org\/pathway\/PA146123006. 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