Pharmaceutical Research

, Volume 30, Issue 6, pp 1513–1524 | Cite as

Systems Pharmacology Modeling of Drug-Induced Modulation of Thyroid Hormones in Dogs and Translation to Human

  • Petra Ekerot
  • Douglas Ferguson
  • Eva-Lena Glämsta
  • Lars B. Nilsson
  • Håkan Andersson
  • Susanne Rosqvist
  • Sandra A. G. VisserEmail author
Research Paper



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.


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.


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.


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.


inter-species extrapolation pharmacokinetics and pharmacodynamics T3 T4 Thyroperoxidase TSH 



Area under the plasma concentration-time curve from time 0–24 h after dosing


Steady state plasma concentration of the MPO inhibitor




Function to describe the drug-induced inhibition of T4 production


Influence of T4 on TSH production


Influence of T4 on TSH turnover


The fraction of T4 that undergoes peripheral conversion to T3


The fraction of T3 converted from T4




Concentration which produces 50% of maximum inhibition of TPO


Maximal inhibition of TPO production


Zero-order production rate of T3


Zero-order production of (the precursor of) T4


Zero-order production of (the precursor of) TSH


First-order rate constant of elimination of T3


First-order rate constant of elimination of T4


First-order rate constant of elimination of TSH


Liquid chromatography with mass spectrometry detection


Lower limit of quantification






MPO inhibitor 1


MPO inhibitor 2


Number of transit compartments


Slope factor of FEED1 relationship


Slope factor of FEED2 relationship


Slope factor in STIM function




Non-active reverse T3


Function to describe TSH influencing the production of T4




Baseline of T3 in plasma




Baseline of T4 in plasma




Thyrotropin-releasing hormone


Thyroid stimulating hormone


Baseline of TSH in plasma


Acknowledgments AND DISCLOSURES

Håkan Eriksson, Anders Viberg, Olof Breuer, Bart Ploeger and Bert Peletier for valuable discussions. The authors state no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Petra Ekerot
    • 1
  • Douglas Ferguson
    • 2
  • Eva-Lena Glämsta
    • 3
  • Lars B. Nilsson
    • 4
  • Håkan Andersson
    • 3
  • Susanne Rosqvist
    • 5
  • Sandra A. G. Visser
    • 6
    Email author
  1. 1.Modeling & Simulation, DMPK CNSPSödertäljeSweden
  2. 2.Modeling & Simulation, DMPK InfectionWalthamUSA
  3. 3.Global Safety AssessmentSödertäljeSweden
  4. 4.Regulatory Bioanalysis, Global DMPKMölndalSweden
  5. 5.Discovery SciencesSödertäljeSweden
  6. 6.Global DMPK, Centre of Excellence, Innovative MedicinesSödertäljeSweden

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