Systems pharmacology modeling of drug-induced modulation of thyroid hormones in dogs and translation to human.

Purpose: To develop a systems pharmacology model based on hormone physiology and pharmacokinetic-pharmacodynamic concepts describing the impact of thyroperoxidase (TPO) inhibition on thyroid hormone homeostasis in the dog and to predict drug-induced changes in thyroid hormones in humans.

Methods: A population model was developed based on a simultaneous analysis of concentration-time data of T₄, T₃ and TSH in dogs following once daily oral dosing for up to 6-months of a myeloperoxidase inhibitor (MPO-IN1) with TPO inhibiting properties. The model consisted of linked turnover compartments for T₄, T₃ and TSH including a negative feedback from T₄ on TSH concentrations.

Results: The model could well describe the concentration-time profiles of thyroid hormones in dog. Successful model validation was performed by predicting the hormone concentrations during 1-month administration of MPO-IN2 based on its in vitro dog TPO inhibition potency. Using human thyroid hormone turnover rates and TPO inhibitory potency, the human T₄ and TSH concentrations upon MPO-IN1 treatment were predicted well.

Conclusions: The model provides a scientific framework for the prediction of drug induced effects on plasma thyroid hormones concentrations in humans via TPO inhibition based on results obtained in in vitro and animal studies.