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Here we present a retrospective pharmacometrics (PMX) based data analysis of the rare disease congenital hypothyroidism (CH) in newborns and infants. Our overall aim is to develop a model that can be applied to optimize dosing in this pediatric patient population since suboptimal treatment of CH during the first 2\u00a0years of life is associated with a reduced intelligence quotient between 10 and 14\u00a0years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2\u00a0years of age. Overall, 505 measurements of free thyroxine (FT4) and 510 measurements of thyrotropin or thyroid-stimulating hormone were available from patients receiving substitution treatment with levothyroxine (LT4). The second goal is to introduce a scale\/location-scale normalization method to merge available FT4 measurements since 34 different postnatal age- and assay-specific laboratory reference ranges were applied. This method takes into account the change of the distribution of FT4 values over time, i.e. a transformation from right-skewed towards normality during LT4 treatment. The third goal is to develop a practical and useful PMX model for LT4 treatment to characterize FT4 measurements, which is applicable within a clinical setting. In summary, a time-dependent normalization method and a practical PMX model are presented. Since there is no on-going or planned development of new pharmacological approaches for CH, PMX based modeling and simulation can be leveraged to personalize dosing with the goal to enhance longer-term neurological outcome in children with the rare disease CH.<\/jats:p>","DOI":"10.1007\/s10928-021-09765-w","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T19:02:46Z","timestamp":1623438166000},"page":"711-723","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study"],"prefix":"10.1007","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-0506","authenticated-orcid":false,"given":"Gilbert","family":"Koch","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Steffens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Leroux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Gotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Schropp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"G\u00e4chter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freya","family":"Bachmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatjana","family":"Welzel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Janner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"L\u2019Allemand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9067-4356","authenticated-orcid":false,"given":"Daniel","family":"Konrad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0559-2597","authenticated-orcid":false,"given":"Gabor","family":"Szinnai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"9765_CR1","unstructured":"Food and Drug Administration. https:\/\/rarediseases.info.nih.gov\/diseases\/pages\/31\/faqs-about-rare-diseases"},{"key":"9765_CR2","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/j.jval.2015.05.008","volume":"18","author":"T Richter","year":"2015","unstructured":"Richter T, Nestler-Parr S, Babela R et al (2015) Rare disease terminology and definitions-a systematic global review: report of the ISPOR rare disease special interest group. 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