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Modeling of levothyroxine in newborns and infants with congenital hypothyroidism : challenges and opportunities of a rare disease multi-center study

Modeling of levothyroxine in newborns and infants with congenital hypothyroidism : challenges and opportunities of a rare disease multi-center study

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KOCH, Gilbert, Britta STEFFENS, Stephanie LEROUX, Verena GOTTA, Johannes SCHROPP, Pascal GÄCHTER, Freya BACHMANN, Tatjana WELZEL, Marco JANNER, 2021. Modeling of levothyroxine in newborns and infants with congenital hypothyroidism : challenges and opportunities of a rare disease multi-center study. In: Journal of pharmacokinetics and pharmacodynamics. Springer. 48(5), pp. 711-723. ISSN 1567-567X. eISSN 1573-8744. Available under: doi: 10.1007/s10928-021-09765-w

@article{Koch2021-10Model-54279, title={Modeling of levothyroxine in newborns and infants with congenital hypothyroidism : challenges and opportunities of a rare disease multi-center study}, year={2021}, doi={10.1007/s10928-021-09765-w}, number={5}, volume={48}, issn={1567-567X}, journal={Journal of pharmacokinetics and pharmacodynamics}, pages={711--723}, author={Koch, Gilbert and Steffens, Britta and Leroux, Stephanie and Gotta, Verena and Schropp, Johannes and Gächter, Pascal and Bachmann, Freya and Welzel, Tatjana and Janner, Marco} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/54279"> <dc:creator>Steffens, Britta</dc:creator> <dc:creator>Welzel, Tatjana</dc:creator> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54279/1/Koch_2-16ixvgr1fs0704.pdf"/> <dc:contributor>Gotta, Verena</dc:contributor> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/54279/1/Koch_2-16ixvgr1fs0704.pdf"/> <dc:contributor>Steffens, Britta</dc:contributor> <dc:creator>Gächter, Pascal</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-07-12T12:44:59Z</dcterms:available> <dc:contributor>Welzel, Tatjana</dc:contributor> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/54279"/> <dc:creator>Gotta, Verena</dc:creator> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by/4.0/"/> <dc:creator>Janner, Marco</dc:creator> <dc:contributor>Bachmann, Freya</dc:contributor> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/39"/> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/39"/> <dc:creator>Leroux, Stephanie</dc:creator> <dc:contributor>Schropp, Johannes</dc:contributor> <dcterms:issued>2021-10</dcterms:issued> <dc:contributor>Leroux, Stephanie</dc:contributor> <dc:creator>Koch, Gilbert</dc:creator> <dc:creator>Bachmann, Freya</dc:creator> <dcterms:abstract xml:lang="eng">Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from several decades measured with different assays. 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 years of life is associated with a reduced intelligence quotient between 10 and 14 years. The first goal is to describe a retrospectively collected dataset consisting of 61 newborns and infants with CH up to 2 years 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.</dcterms:abstract> <dc:contributor>Janner, Marco</dc:contributor> <dc:language>eng</dc:language> <dc:contributor>Gächter, Pascal</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-07-12T12:44:59Z</dc:date> <dcterms:title>Modeling of levothyroxine in newborns and infants with congenital hypothyroidism : challenges and opportunities of a rare disease multi-center study</dcterms:title> <dc:contributor>Koch, Gilbert</dc:contributor> <dc:creator>Schropp, Johannes</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:rights>Attribution 4.0 International</dc:rights> </rdf:Description> </rdf:RDF>

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