{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:20:47Z","timestamp":1787671247546,"version":"build-2736575974"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The mainstay of treatment for infants with hypoxic\u2010ischemic encephalopathy (HIE) is cooling. Caffeine may be an important adjunct to cooling and provide neuroprotection via its anti\u2010inflammatory and anti\u2010oxidative properties. This study aimed to characterize caffeine pharmacokinetics in term infants with HIE receiving cooling.<\/jats:p><jats:p>In this phase 1, dose\u2010escalating study, enrolled infants received IV caffeine 20 mg\/kg followed by up to two daily doses of 5 or 10 mg\/kg. A population pharmacokinetic analysis was performed using NONMEM (v7.5). The effects of clinical covariates, including cooling, on pharmacokinetic parameters were evaluated. Dosing simulations were performed to evaluate the percentage of plasma exposures in the reference range (15\u201025 mg\/L).<\/jats:p><jats:p>Seventeen infants were included in model development. A one\u2010compartment model best fit the data. Population clearance was 0.445 L\/h\/70 kg and volume of distribution was 87.1 L\/70 kg. Current dosing regimens (20 mg\/kg followed by 5 mg\/kg) resulted in 89.5% of infants having at least one simulated exposure below the reference range across the dosing interval. Dosing regimens of 30 mg\/kg followed by 5 or 10 mg\/kg were predicted to result in more than half of infants achieving simulated exposures in the reference range, with \u22642% of infants having simulated exposures in the toxic range (&gt;46 mg\/L).<\/jats:p><jats:p>Term infants with HIE had similar weight\u2010normalized clearance but higher weight\u2010normalized volume of distribution compared to prior studies in preterm infants without HIE or cooling. While exposure targets for neuroprotection in HIE are unknown, this phase 1 study suggests alternate dosing strategies should be considered in future studies.<\/jats:p>","DOI":"10.1002\/jcph.70004","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:40:43Z","timestamp":1739356843000},"page":"933-943","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Population Pharmacokinetics of Caffeine in Infants with Hypoxic\u2010Ischemic Encephalopathy: A Phase I, Dose\u2010Escalating Trial"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-1789","authenticated-orcid":false,"given":"Elizabeth J","family":"Thompson","sequence":"first","affiliation":[{"name":"Duke Clinical Research Institute  Durham NC USA"},{"name":"University of North Carolina Eshelman School of Pharmacy  Chapel Hill NC USA"},{"name":"Department of Pediatrics Duke University School of Medicine  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5522-5686","authenticated-orcid":false,"given":"Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-5819","authenticated-orcid":false,"given":"Julie","family":"Dumond","sequence":"additional","affiliation":[{"name":"University of North Carolina Eshelman School of Pharmacy  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7056-8759","authenticated-orcid":false,"given":"Christoph P","family":"Hornik","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute  Durham NC USA"},{"name":"University of North Carolina Eshelman School of Pharmacy  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Kilborn","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute  Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4052-3215","authenticated-orcid":false,"given":"Matthew M","family":"Laughon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of North Carolina School of Medicine  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9403-381X","authenticated-orcid":false,"given":"Wesley M","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of North Carolina School of Medicine  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2014.3269"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7218"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2013.878694"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21008"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0028\u20103908(97)00139\u20101"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199606000-00005"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3181898b6f"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2020.101178"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0148607113499590"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2020.101183"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.775"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14136"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12883"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612821666150901110929"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpedi.1980.02130170045015"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20103476(79)80047\u20105"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2016\u20100403A"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551\u20106776\u201012.4.212"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0009\u20109236(97)90097\u20107"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.842544"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2016.03.018"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2382"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41372\u2010023\u201001752\u2010y"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/bf01061844"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13001"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050276"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14483"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.13240"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390\u2010022\u201002172\u2010y"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102710.1991.tb00316.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010023\u201000851\u20100"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0247403"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.112.000858"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pedneo.2017.10.007"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12020288"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.2165\/11319360\u2010000000000\u201000000"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1917"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12711"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.724161"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201036653\u20109"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1089\/jcr.2016.0012"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcps050929"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.70004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T01:57:14Z","timestamp":1750989434000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.70004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,12]]},"references-count":42,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1002\/jcph.70004"],"URL":"https:\/\/doi.org\/10.1002\/jcph.70004","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,12]]},"assertion":[{"value":"2024-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}