Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease

Frontiers in Medicine

Medicine

Johannes Schropp¹  Freya Bachmann¹  Dagmar l'Allemand²  Daniel Konrad³  Marco Janner⁴  Fabien Claude⁵  Pascal Gächter⁵  Gabor Szinnai⁶  Britta Steffens⁷  Verena Gotta⁷  Gilbert Koch⁷  Tatjana Welzel⁷  Marc Pfister⁸ 

[1] Department of Mathematics and Statistics, University of Konstanz, Konstanz, Germany;Department of Pediatric Endocrinology and Diabetology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland;Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland;Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;Pediatric Endocrinology and Diabetology, University Children's Hospital Basel UKBB, University of Basel, Basel, Switzerland;Pediatric Endocrinology and Diabetology, University Children's Hospital Basel UKBB, University of Basel, Basel, Switzerland;Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland;Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel UKBB, University of Basel, Basel, Switzerland;Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel UKBB, University of Basel, Basel, Switzerland;Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland;

关键词: Graves' disease (GD);    pediatric rare diseases;    hyperthyroidism;    thyrotoxicosis;    carbimazole monotherapy;    block-and-replace therapy;    mathematical model;    pharmacometrics model;   

DOI  :  10.3389/fmed.2023.1099470

 received in 2022-11-15, accepted in 2023-03-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

ObjectivesGraves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy.MethodsRetrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis.ResultsData from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity.DiscussionWe present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.

【 授权许可】

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Copyright © 2023 Steffens, Koch, Gächter, Claude, Gotta, Bachmann, Schropp, Janner, l'Allemand, Konrad, Welzel, Szinnai and Pfister.