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.
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 dogTPO 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.
Authors: Teresa Collins; Kelly Gray; Michal Bista; Matt Skinner; Christopher Hardy; Haiyun Wang; Jerome T Mettetal; Alexander R Harmer Journal: Br J Pharmacol Date: 2018-01-18 Impact factor: 8.739
Authors: Gabriel Helmlinger; Victor Sokolov; Kirill Peskov; Karen M Hallow; Yuri Kosinsky; Veronika Voronova; Lulu Chu; Tatiana Yakovleva; Ivan Azarov; Daniel Kaschek; Artem Dolgun; Henning Schmidt; David W Boulton; Robert C Penland Journal: CPT Pharmacometrics Syst Pharmacol Date: 2019-06-11
Authors: Erica L Bradshaw; Mary E Spilker; Richard Zang; Loveleena Bansal; Handan He; Rhys D O Jones; Kha Le; Mark Penney; Edgar Schuck; Brian Topp; Alice Tsai; Christine Xu; Marjoleen J M A Nijsen; Jason R Chan Journal: CPT Pharmacometrics Syst Pharmacol Date: 2019-10-25