Mechanism-based Pharmacokinetic-Pharmacodynamic Feedback Model of Thyroid Hormones after Inhibition of Thyroperoxidase in the Dog. Cross-species Prediction of Thyroid Hormone Profiles in Rats and Humans.
Petra Ekerot (1), Douglas Ferguson (2), Sandra A. G. Visser (3)
(1) Modelling & Simulation, DMPK iMed CNSP AstraZeneca R&D Södertälje, Sweden, (2) Modelling & Simulation, DMPK iMed Infection, AstraZeneca R&D Boston, USA, (3) Global DMPK Centre of Excellence, AstraZeneca R&D, Södertälje, Sweden
Objectives: Thyroperoxidase (TPO) is an enzyme involved in the synthesis of T4 and T3 in the follicular cells of the thyroid gland. Inhibition of TPO will result in decreased plasma T4 and T3 and elevated TSH (thyroid-stimulating hormone) levels. The aim was to develop a mechanism-based pharmacokinetic-pharmacodynamic feedback model to describe the impact of TPO inhibition on thyroid hormone homeostasis in the dog and to predict thyroid hormone profiles in rats and humans based upon inter-species differences in hormone degradation rates and in vitro IC50 values for TPO inhibition.
Methods: The PK/PD model was developed based on a simultaneous analysis of concentration-time data of T4, T3 & TSH at multiple dose levels in the dogs following once daily oral dosing of a TPO inhibitor (Cmpd I) for up to 6 months. The model consists of linked turnover compartments for T4, T3 & TSH. First-order degradation rate constants for T4 & T3 (KT4 & KT3) were fixed at known physiological values. The fraction (Fr) of T4 peripherally converted to T3 was estimated. Homeostatic feedback mechanisms were included to explain the negative feedback from T4 on TSH levels. Cmpd I was assumed to inhibit the synthesis rate of T4 using an Imax function. Model development and fitting was performed using NONMEM VII. Berkeley Madonna was used to predict rat and human thyroid hormone profiles.
Results: The PK/PD model could well describe the concentration-time profiles of T4, T3 and TSH in the dog after repeated administration of Cmpd I. The validity of the model was confirmed by successfully predicting T4, T3 & TSH levels for Cmpd II in the dog on basis of in vitro IC50 for TPO inhibition. By altering KT4 and KT3 to reflect interspecies differences in hormone t1/2, adjusting in vivo IC50 (to maintain a constant in vitro IC50/in vivo IC50 ratio cross-species) and adjusting fraction of T3 converted from T4, the model successfully predicted the observed T4 & TSH profiles in rat and human for Cmpd I.
Conclusions: The proposed mechanism-based PK/PD feedback model provides a scientific basis for the prediction of TPO inhibition mediated effects on plasma thyroid hormones levels in humans based on results obtained in animals studies.
