{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:35:32Z","timestamp":1790336132212,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Drug disposition in children may vary from adults due to age\u2010related variation in drug metabolism. Microdose studies present an innovation to study pharmacokinetics (PK) in paediatrics; however, they should be used only when the PK is dose linear. We aimed to assess dose linearity of a [<jats:sup>14<\/jats:sup>C]midazolam microdose, by comparing the PK of an intravenous (IV) microtracer (a microdose given simultaneously with a therapeutic midazolam dose), with the PK of a single isolated microdose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Preterm to 2\u2010year\u2010old infants admitted to the intensive care unit received [<jats:sup>14<\/jats:sup>C]midazolam IV as a microtracer or microdose, followed by dense blood sampling up to 36\u00a0hours. Plasma concentrations of [<jats:sup>14<\/jats:sup>C]midazolam and [<jats:sup>14<\/jats:sup>C]1\u2010hydroxy\u2010midazolam were determined by accelerator mass spectrometry. Noncompartmental PK analysis was performed and a population PK model was developed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 15 infants (median gestational age 39.4 [range 23.9\u201341.4] weeks, postnatal age 11.4 [0.6\u201349.1] weeks), 6 received a microtracer and 9 a microdose of [<jats:sup>14<\/jats:sup>C]midazolam (111\u00a0Bq\u00a0kg<jats:sup>\u22121<\/jats:sup>; 37.6\u00a0ng\u00a0kg<jats:sup>\u22121<\/jats:sup>). In a 2\u2010compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the microdose and microtracer, nor in the area under curve ratio [<jats:sup>14<\/jats:sup>C]1\u2010OH\u2010midazolam\/[<jats:sup>14<\/jats:sup>C]midazolam, showing the PK of midazolam to be linear within the range of the therapeutic and microdoses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data support the dose linearity of the PK of an IV [<jats:sup>14<\/jats:sup>C]midazolam microdose in children. Hence, a [<jats:sup>14<\/jats:sup>C]midazolam microdosing approach may be used as an alternative to a therapeutic dose of midazolam to study developmental changes in hepatic CYP3A activity in young children.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14047","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T17:54:46Z","timestamp":1562176486000},"page":"2332-2340","source":"Crossref","is-referenced-by-count":15,"title":["Dose\u2010linearity of the pharmacokinetics of an intravenous [<sup>14<\/sup>C]midazolam microdose in children"],"prefix":"10.1111","volume":"85","author":[{"given":"Bianca D.","family":"van Groen","sequence":"first","affiliation":[{"name":"Erasmus MC Sophia Children's Hospital  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter H.","family":"Vaes","sequence":"additional","affiliation":[{"name":"TNO  Zeist The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. Kevin","family":"Park","sequence":"additional","affiliation":[{"name":"University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6006-1567","authenticated-orcid":false,"given":"Elke H.J.","family":"Krekels","sequence":"additional","affiliation":[{"name":"Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"van Duijn","sequence":"additional","affiliation":[{"name":"TNO  Zeist The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenne\u2010Triin","family":"K\u00f5rgvee","sequence":"additional","affiliation":[{"name":"University of Tartu  Tartu Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wioleta","family":"Maruszak","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grzegorz","family":"Grynkiewicz","sequence":"additional","affiliation":[{"name":"Pharmaceutical Research Institute  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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