Enhanced pharmacometrics model utilizes heart rate to monitor thyroid function in pediatric Graves’ disease under pharmacotherapy
Britta Steffens (1), Gilbert Koch (1), Fabien Claude (2), Freya Bachmann (3), Johannes Schropp (3), Gabor Szinnai (2,4), Marc Pfister (1,4)
(1) Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital UKBB, Basel, Switzerland, (2) Pediatric Endocrinology and Diabetology, University of Basel Children’s Hospital UKBB, Basel, Switzerland, (3) Department of Mathematics and Statistics, University of Konstanz, Konstanz, Germany, (4) Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland
Objectives:
Graves’ disease (GD) with onset in childhood or adolescence is a serious pediatric rare disease (ORPHA:525731). Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. Goal of pharmacotherapy is normalization of free thyroxine (FT4) levels within 8 weeks. Current treatment approaches use anti-thyroid drugs such as carbimazole in monotherapy or in combination with thyroxine hormone substitutes, i.e., levothyroxine as block-and-replace therapy. Recently, we developed a pharmacometrics (PMX) model characterizing FT4 kinetics in children and adolescents with GD under both pharmacotherapy approaches [1]. Dose finding in pediatric GD is complex due to highly variable disease severity at diagnosis and fluctuating individual disease dynamics during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) is a useful clinical marker to monitor thyroid activity under pharmacotherapy. In adults with GD, feasibility of monitoring HR using wearable devices was demonstrated in a recent prospective study [2]. To further facilitate implementation of our PMX model [1] in clinical practice, we extend existing PMX model to describe relation between changing FT4 and tachycardia (“HR dynamics”) in children with various GD severity and dynamics under both treatment approaches.
Our objectives are (i) to perform descriptive analysis of retrospectively collected data from children and adolescents with GD during first 120 days of treatment and (ii) to extend existing PMX model for FT4 kinetics in pediatric patients with various disease severity of GD under pharmacotherapy by linking FT4 kinetics with “HR dynamics” and including a weight (WT) progression component.
Methods:
Retrospectively collected clinical (resting HR during consultation) and laboratory data (FT4) from children with GD during the first 120 days of treatment at four pediatric hospitals in Switzerland were analyzed. PMX model is developed in the non-linear mixed effects modeling framework consisting of three differential equations characterizing WT progression, and linking FT4 kinetics with HR dynamics, and incorporating clinically relevant individual patient characteristics. GD severity groups were defined based on FT4 at diagnosis according to current guidelines [3].
Results: Data from 41 children and adolescents with GD (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements, 132 HR measurements, and 165 WT measurements, 119 paired measurements, were analyzed and used for model development. Pediatric patients showed a median FT4 at diagnosis of 59.6 [IQR 44.5, 73.0] pmol/l, a median HR at diagnosis of 112 [IQR 100, 128] bpm, and a median WT at diagnosis of 34.5 [IQR 26.9, 49.0] kg, and we had equal numbers of mild (13), moderate (14) and severe (14) GD at diagnosis. Based on FT4 at diagnosis, available patient data gave rise to a significant difference in HR at diagnosis (p < 0.01) between the three GD severity groups but not in WT at diagnosis. Final PMX computer model accurately predicted WT progression, FT4 kinetics, and HR dynamics for each GD patient during the first 120 days of treatment, accounting for clinically relevant covariate effects, such as age, gender, and GD severity.
Conclusions:
Enhanced clinically practical PMX model simultaneously predicts individual WT progression, and individual HR and disease dynamics under pharmacotherapy. This predictive PMX model is expected to facilitate personalized pharmacotherapy and has the potential to mitigate risk for under- or overdosing of anti-thyroid drugs in children and adolescents with GD. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD patients.
References:
[1] Steffens B, Koch G, Gaechter P, Claude F, Gotta V, Bachmann F, Schropp J, Janner M, l’Allemand D, Konrad D, Welzel T, Szinnai G, Pfister M (2023). Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves’ disease. Frontiers in Medicine (accepted)
[2] Lee J-E, Lee DH, Oh TJ, Kim KM, Choi SH, Lim S, Park YJ, Park DJ, Jang HC, Moon JH (2018). Clinical feasibility of monitoring resting heart rate using a wearable activity tracker in patients with thyrotoxicosis: prospective longitudinal observational study. JMIR MHealth and UHealth, 6(7), e9884
[3] Leger J, Oliver I, Rodrigue D, Lambert A-S, Coutant R (2018). Graves’ disease in children. Ann Endocrinol, 79(6), 647-655.