Advertisement

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. Visser
Research Paper

ABSTRACT

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.

KEY WORDS

inter-species extrapolation pharmacokinetics and pharmacodynamics T3 T4 Thyroperoxidase TSH 

ABBREVIATIONS

AUC0-24

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

Css

Steady state plasma concentration of the MPO inhibitor

DIT

Diiodotyrosine

DRUG

Function to describe the drug-induced inhibition of T4 production

FEED1

Influence of T4 on TSH production

FEED2

Influence of T4 on TSH turnover

fr

The fraction of T4 that undergoes peripheral conversion to T3

Fraction

The fraction of T3 converted from T4

HPT

Hypothalamic-pituitary-thyroid

IC50

Concentration which produces 50% of maximum inhibition of TPO

Imax

Maximal inhibition of TPO production

kinT3

Zero-order production rate of T3

kinT4

Zero-order production of (the precursor of) T4

kinTSH

Zero-order production of (the precursor of) TSH

kT3

First-order rate constant of elimination of T3

kT4

First-order rate constant of elimination of T4

kTSH

First-order rate constant of elimination of TSH

LC-MS/MS

Liquid chromatography with mass spectrometry detection

LLOQ

Lower limit of quantification

MIT

Monoiodotyrosine

MPO

Myeloperoxidase

MPO-IN1

MPO inhibitor 1

MPO-IN2

MPO inhibitor 2

n

Number of transit compartments

NF1

Slope factor of FEED1 relationship

NF2

Slope factor of FEED2 relationship

NF3

Slope factor in STIM function

PKPD

Pharmacokinetic-pharmacodynamic

rT3

Non-active reverse T3

STIM

Function to describe TSH influencing the production of T4

T3

Triiodothyronine

T3,BL

Baseline of T3 in plasma

T4

Thyroxine

T4,BL

Baseline of T4 in plasma

TPO

Thyroperoxidase

TRH

Thyrotropin-releasing hormone

TSH

Thyroid stimulating hormone

TSHBL

Baseline of TSH in plasma

Notes

Acknowledgments AND DISCLOSURES

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

REFERENCES

  1. 1.
    Guyton AC, Hall JE. Textbook of medicial physiology. Eleventhth ed. Philadelphia: Elsevier Inc; 2006.Google Scholar
  2. 2.
    Zoeller RT, Tan SW, Tyl RW. General Background on the Hypothalamic-Pituitary-Thyroid (HPT) Axis. Crit Rev Toxicol 2007 01/01; 2012/08;37(1, 2):11–53.Google Scholar
  3. 3.
    Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s Principles of Internal Medicine, 15th Edition: McGraw-Hill Companies, Inc; 2001. p. 2060–2064.Google Scholar
  4. 4.
    Fliers E, Alkemade A, Wiersinga WM, Swaab DF. Hypothalamic thyroid hormone feedback in health and disease. In: Kalsbeek, Fliers E, Hofman, Swaab, Van Someren, Buys, editors. Progress in Brain Research: Elsevier; 2006. p. 189–207.Google Scholar
  5. 5.
    Ridgway EC, Weintraub BD, Maloof F. Metabolic clearance and production rates of human thyrotropin. J Clin Invest. 1974;53(3):895–903.PubMedCrossRefGoogle Scholar
  6. 6.
    Nussey S, Whitehead S. An integrated Approach. Oxford: Bios Scientific Publishers. 2001.Google Scholar
  7. 7.
    McGuire RA, Hays MT. A kinetic model of human thyroid hormones and their conversion products. J Clin Endocrinol Metab. 1981;53(4):852–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Belshaw BE, Barandes M, Becker DV, Berman M. A model of iodine kinetics in the dog. Endocrinology. 1974;95(4):1078–93.PubMedCrossRefGoogle Scholar
  9. 9.
    Kaptein EM, Moore GE, Ferguson DC, Hoenig M. Thyroxine and triiodothyronine distribution and metabolism in thyroxine-replaced athyreotic dogs and normal humans. Am J Physiol. 1993;264(1 Pt 1):E90–E100.PubMedGoogle Scholar
  10. 10.
    van der Graaf PH, Benson N. Systems pharmacology: bridging systems biology and pharmacokinetics-pharmacodynamics (PKPD) in drug discovery and development. Pharm Res. 2011;28(7):1460–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Math Biosci. 2008;212(1):22–53.PubMedCrossRefGoogle Scholar
  12. 12.
    Hatakeyama T, Yagi H. Computer simulation for hormones related to primary thyropathy. Biol Cybern. 1985;52(4):259–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Saratchandran P, Carson ER, Reeve J. An improved mathematical model of human thyroid hormone regulation. Clin Endocrinol (Oxf). 1976;5(5):473–83.CrossRefGoogle Scholar
  14. 14.
    DiStefano 3rd JJ, Stear EB. On identification of hypothalamo-hypophysial control and feedback relationships with the thyroid gland. J Theor Biol. 1968;19(1):29–50.PubMedCrossRefGoogle Scholar
  15. 15.
    Danziger L, Elmergreen G. Mathematical models of endocrine systems. Bull Math Biol. 1957;19(1):9–18.Google Scholar
  16. 16.
    Hays MT, Broome MR, Turrel JM. A multicompartmental model for iodide, thyroxine, and triiodothyronine metabolism in normal and spontaneously hyperthyroid cats. Endocrinology. 1988;122(6):2444–61.PubMedCrossRefGoogle Scholar
  17. 17.
    McLanahan ED, Andersen ME, Fisher JW. A biologically based dose–response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat: evaluation of iodide deficiency. Toxicol Sci. 2008;102(2):241–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Merrill EA, Clewell RA, Robinson PJ, Jarabek AM, Gearhart JM, Sterner TR, et al. PBPK model for radioactive iodide and perchlorate kinetics and perchlorate-induced inhibition of iodide uptake in humans. Toxicol Sci. 2005;83(1):25–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Eisenberg M, Samuels M, DiStefano 3rd JJ. Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis. Thyroid. 2008;18(10):1071–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Eisenberg M, Samuels M, DiStefano 3rd JJ. L-T4 bioequivalence and hormone replacement studies via feedback control simulations. Thyroid. 2006;16(12):1279–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Eisenberg MC, Santini F, Marsili A, Pinchera A, DiStefano 3rd JJ. TSH regulation dynamics in central and extreme primary hypothyroidism. Thyroid. 2010;20(11):1215–28.PubMedCrossRefGoogle Scholar
  22. 22.
    Mukhopadhyay B, Bhattacharyya R. A mathematical model describing the thyroid-pituitary axis with time delays in hormone transportation. Appl Math. 2006;6:549–64.CrossRefGoogle Scholar
  23. 23.
    Dietrich JW, Boehm BO. Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybern Syst. 2006;1:269–74.Google Scholar
  24. 24.
    Dietrich JW, Tesche A, Pickardt CR, Mitzdorf U. Thyrotropic feedback control: evidence of an additional ultrashort feedback loop from fractal analysis. Cybern Syst 2004 06/01; 2012/08;35(4):315–331.Google Scholar
  25. 25.
    Kimura S, Ikeda-Saito M. Human myeloperoxidase and thyroid peroxidase, two enzymes with separate and distinct physiological functions, are evolutionarily related members of the same gene family. Proteins. 1988;3(2):113–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Malle E, Furtmüller PG, Sattler W, Obinger C. Myeloperoxidase: a target for new drug development? Br J Pharmacol. 2007;152(6):838–54.PubMedCrossRefGoogle Scholar
  27. 27.
    Nilsson LB, Eklund G. Direct quantification in bioanalytical LC–MS/MS using internal calibration via analyte/stable isotope ratio. J Pharm Biomed Anal. 2007;43(3):1094–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711–26.PubMedCrossRefGoogle Scholar
  29. 29.
    Ganjam VK, Wyckoff JT, Comerci CA, Ravis WR. Recrudescence of extra‐thyroidal tissue. T4 and T3 kinetics following thyroidectomy and effect of replacement therapy in the canine. Fed Proc 1980;39:947.Google Scholar
  30. 30.
    Kinlaw WB, Schwartz HL, Oppenheimer JH. Decreased serum triiodothyronine in starving rats is due primarily to diminished thyroidal secretion of thyroxine. J Clin Invest. 1985;75(4):1238–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Nicoloff JT, Low JC, Dussault JH, Fisher DA. Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J Clin Invest. 1972;51(3):473–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National health and nutrition examination survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab. 2007;92(11):4236–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Liu Y, Liu B, Xie J, Liu YX. A new mathematical model of hypothalamo-pituitary-thyroid axis. Math Comput Model. 1994;19(9):81–90.CrossRefGoogle Scholar
  34. 34.
    Li G, Liu B, Liu Y. A dynamical model of the pulsatile secretion of the hypothalamo-pituitary-thyroid axis. Biosystems. 1995;35(1):83–92.PubMedCrossRefGoogle Scholar
  35. 35.
    Hays MT, McGuire RA. Distribution of subcutaneous thyroxine, triiodothyronine, and albumin in man: comparison with intravenous administration using a kinetic model. J Clin Endocrinol Metab. 1980;51(5):1112–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Kaplan MM. The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function. Neuroendocrinology. 1984;38(3):254–60.PubMedCrossRefGoogle Scholar

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
  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

Personalised recommendations