{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:34:24Z","timestamp":1790213664542,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,6,21]],"date-time":"2018-06-21T00:00:00Z","timestamp":1529539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["Grant agreement n\u00b0223614"],"award-info":[{"award-number":["Grant agreement n\u00b0223614"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["223\u2009614"],"award-info":[{"award-number":["223\u2009614"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neonates were randomized 1:1 to fluconazole (loading dose 25\u00a0mg kg<jats:sup>\u20131<\/jats:sup>; maintenance dose 12\u00a0mg kg<jats:sup>\u20131<\/jats:sup> day<jats:sup>\u20131<\/jats:sup> or 20\u00a0mg kg<jats:sup>\u20131<\/jats:sup> day<jats:sup>\u20131<\/jats:sup>, respectively, for infants &lt;30\u00a0weeks or \u226530\u00a0weeks\u2019 corrected gestational age) or micafungin (loading dose 15\u00a0mg kg<jats:sup>\u20131<\/jats:sup> day<jats:sup>\u20131<\/jats:sup>; maintenance dose 10\u00a0mg kg<jats:sup>\u20131<\/jats:sup> day<jats:sup>\u20131<\/jats:sup>). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36\u00a0weeks\u2019 corrected gestational age or hospital discharge.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty\u2010six neonates were enrolled. The median (range) gestational age was 28.2 (24.1\u201340.1) and 26.8 (23.5\u201340.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h<jats:sup>\u20131<\/jats:sup> kg<jats:sup>\u20131<\/jats:sup>) and volume of distribution (l kg<jats:sup>\u20131<\/jats:sup>) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration\u2013time curve target attainment rate in neonates.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13628","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T08:44:21Z","timestamp":1525941861000},"page":"1989-1999","source":"Crossref","is-referenced-by-count":37,"title":["Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open\u2010label clinical trial"],"prefix":"10.1111","volume":"84","author":[{"given":"S.","family":"Leroux","sequence":"first","affiliation":[{"name":"Department of Pediatric Pharmacology and Pharmacogenetics Clinical Investigation Center 1426 Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-7067","authenticated-orcid":false,"given":"E.","family":"Jacqz\u2010Aigrain","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pharmacology and Pharmacogenetics Clinical Investigation Center 1426 Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Elie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Legrand","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pharmacology and Pharmacogenetics Clinical Investigation Center 1426 Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Barin\u2010Le Guellec","sequence":"additional","affiliation":[{"name":"EA4245, Facult\u00e9 de M\u00e9decine Universit\u00e9 Fran\u00e7ois Rabelais  Tours France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Aurich","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pharmacology and Pharmacogenetics Clinical Investigation Center 1426 Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Biran","sequence":"additional","affiliation":[{"name":"UMR 1141 INSERM, Universit\u00e9 Paris 7\u2010Diderot, Neonatal Intensive Care Unit Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Dusang","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit CHU de La R\u00e9union  Saint Pierre La R\u00e9union France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Goudjil","sequence":"additional","affiliation":[{"name":"Neonatal Care Unit CHU Amiens  Amiens France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Coopman","sequence":"additional","affiliation":[{"name":"Centre d'Investigation Clinique, CIC1403 Lille University Hospital  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Garcia Sanchez","sequence":"additional","affiliation":[{"name":"Hospital Universitario de Salamanca  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pharmacology and Pharmacogenetics Clinical Investigation Center 1426 Robert\u2010Debr\u00e9 Paediatric Hospital, Assistance Publique H\u00f4pitaux de Paris  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Manzoni","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit S. Anna Hospital  Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the FP7 TINN (Treat Infections in NeoNates) consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,6,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12578"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2013.04.034"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.112.3.634"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2004-2292"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2009-3412"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2005.082024"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12380"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2015.1031108"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12040"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00148581-200709050-00004"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2008.154385"},{"key":"e_1_2_10_13_1","unstructured":"Diflucan.Summary of Product Characteristics. European Medicines Agency[online]. Available athttp:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Referrals_document\/Diflucan_30\/WC500121908.pdf (last accessed 15 September 2017)."},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1415-2"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2012-303350"},{"key":"e_1_2_10_16_1","unstructured":"Mycafungin.Summary of Product Characteristics. European Medicines Agency [online]. Available athttps:\/\/www.medicines.org.uk\/emc\/product\/6315\/smpc(last accessed 9 June 2018)."},{"key":"e_1_2_10_17_1","unstructured":"European Medicines Agency.Mycamine: EPAR\u2010Summary of product characteristics [online]. Available at:http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-Public_assessment_report\/human\/000734\/WC500031079.pdf(last accessed 9 June 2018)."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000000434"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-014-0227-3"},{"key":"e_1_2_10_20_1","unstructured":"International Conference on Harmonization of technical requirements for registration of pharmaceutical for human use. Current Step 4 \u2010 Version dated 10 June 1996. Available athttps:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E6\/E6_R1_Guideline.pdf(last accessed 10 June 2018)."},{"key":"e_1_2_10_21_1","unstructured":"International Conference of Harmonisation for Better Health.E11 Clinical Trials in Pediatric Population [online].https:\/\/ec.europa.eu\/health\/sites\/health\/files\/files\/eudralex\/vol-10\/ethical_considerations_en.pdf(last accessed 9 June 2018)."},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00569-08"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0169-7"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1086\/524063"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2011.545345"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01679-09"},{"key":"e_1_2_10_27_1","unstructured":"International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use.Harmonised tripartite guideline. Clinical safety data management: Definitions and standards for expedited reporting E2A [online].1994. Available athttps:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Efficacy\/E2A\/Step4\/E2A_Guideline.pdf(last accessed 15 September 2017)"},{"key":"e_1_2_10_28_1","unstructured":"International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.MedDRA Term Selection: Points to consider. ICH\u2010Endorsed Guide for MedDRA Users. Release 4.11 Based on MedDRA Version 19.0 [online]. Available athttps:\/\/www.meddra.org\/sites\/default\/files\/guidance\/file\/9491\u20101900_termselptc_r4_11_mar2016_0.pdf(last accessed 5 September 2017)"},{"key":"e_1_2_10_29_1","unstructured":"World Health Organization.Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment [online]. Available at:https:\/\/www.whocc.no\/atc_ddd_index_and_guidelines\/guidelines\/(last accessed 10 September 2017)"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2008-2654"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-011-1565-8"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1086\/313749"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/civ933","article-title":"Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America","volume":"15","author":"Pappas PG","year":"2016","journal-title":"Clin Infect Dis"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0b013e318202cbb3"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0b013e31819f1f50"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.8.3171-3177.2005"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00741-06"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.200"},{"key":"e_1_2_10_39_1","first-page":"CD000503","article-title":"Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants","volume":"3","author":"Bell EF","year":"2001","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.06.039"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1468-2"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12887-016-0605-y"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.03.036"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbcp.13628","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.13628","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T11:33:41Z","timestamp":1695036821000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.13628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,21]]},"references-count":42,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,9]]}},"alternative-id":["10.1111\/bcp.13628"],"URL":"https:\/\/doi.org\/10.1111\/bcp.13628","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,21]]}}}