title: Systems pharmacology modeling of drug-induced modulation of thyroid hormones in dogs and translation to human.
abstract: OBJECTIVE
  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.
authors.affiliation: Modeling & Simulation, DMPK CNSP, AstraZeneca R&D, 15185 Södertälje, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Ekerot
authors.forename: Douglas
authors.initials: D
authors.lastname: Ferguson
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Glämsta
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nilsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Andersson
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosqvist
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D014284:Triiodothyronine; D013972:Thyrotropin; D009195:Peroxidase; D013974:Thyroxine