A PBPK-QSP model for regulation of thyroid hormones in Allan-Herndon Dudley Syndrome
Authors: Gupta Kajal , Cristofoletti Rodrigo 
Published: February 2025

Authors: Kajal Gupta, Rodrigo CristofolettiInstitution: University of Florida, Centre for Pharmacometrics and Systems Biology, Lake Nona, Orlando.Objective: Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked neurodevelopmental disorder characterized by abnormal serum thyroid hormone concentrations due to a mutation in the SLC16A2 gene, encoding for the monocarboxylate-8 (MCT-8) transporter, which is responsible for thyroid hormone transport to the brain. To elucidate the mechanisms underlying the unusual serum hormone concentrations in AHDS patients and explore potential pharmacological interventions, we built a physiology base pharmacokinetic-quantitative systems pharmacology (PBPK-QSP) model with transporter-mediated permeability across BBB. Such a model will help understand the exposure response of the drug in these patients.Methodology: The PBPK-QSP model integrates the pharmacokinetics of triiodothyroacetic acid (Triac), a therapeutic analog of thyroid hormone, to elucidate its impact on thyroid hormone homeostasis. The model comprises two sub-models: a 4-brain model accounting for impaired hormone transport (transporter limited permeability) to the CNS, and a thyroid tissue sub-model capturing hormone kinetics. By incorporating chemical-specific Triac PBPK and thyroid hormone kinetics, our model quantitatively links drug dose to serum hormone levels and their regulation through the hypothalamic-pituitary thyroid axis feedback mechanism.Results: The simulation results of the four-brain model demonstrate the distribution of thyroid hormones within the CNS of both healthy individuals and AHDS patients, considering the impaired MCT-8 function associated with the AHDS. The simulations for hormone regulation are generated empirically, with a random variability, which helps us understand the implementation of effect of Triac on hormone regulation cycle. Conclusion: Integration of Triac PK with hormone regulation dynamics, the model offers valuable insights into the systemic distribution of thyroid hormones and the pharmacological effects of Triac in AHDS patients. This approach not only enhances our understanding of AHDS pathophysiology but also provides a framework for optimizing drug therapy and improving patient outcomes. Additionally, the model can be extended to evaluate potential drug-transporter interactions, such as the effect of tyrosine kinase inhibitors on MCT-8, which may affect thyroid hormone homeostasis. The model will be applied to get a quantitative understanding of other thyroid related diseases like Hashimoto's thyroiditis, hyper/hypothyroidism, and postpartum thyroiditis.Citations: 1. Wolff, T.M., Veil, C., Dietrich, J.W. and Müller, M.A., 2022. Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome. Frontiers in Endocrinology, 13, p.882788.2. Hoermann, R., Pekker, M.J., Midgley, J.E. and Dietrich, J.W., 2023. The role of supporting and disruptive mechanisms of FT3 homeostasis in regulating the hypothalamic–pituitary–thyroid axis. Therapeutic advances in endocrinology and metabolism, 14, p.20420188231158163.3. Handa, S., Hassan, I., Gilbert, M. and El-Masri, H., 2021. Mechanistic computational model for extrapolating in vitro thyroid peroxidase (TPO) inhibition data to predict serum thyroid hormone levels in rats. Toxicological Sciences, 183(1), pp.36-48.