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

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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.

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Abbreviations

AUC0-24 :

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

C ss :

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

IC 50 :

Concentration which produces 50% of maximum inhibition of TPO

I max :

Maximal inhibition of TPO production

kin T3 :

Zero-order production rate of T3

kin T4 :

Zero-order production of (the precursor of) T4

kin TSH :

Zero-order production of (the precursor of) TSH

k T3 :

First-order rate constant of elimination of T3

k T4 :

First-order rate constant of elimination of T4

k TSH :

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

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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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Authors and Affiliations

  1. Modeling & Simulation, DMPK CNSP, AstraZeneca R&D, 151 85, Södertälje, Sweden

    Petra Ekerot

  2. Modeling & Simulation, DMPK Infection, Waltham, MA, USA

    Douglas Ferguson

  3. Global Safety Assessment, AstraZeneca R&D, 151 85, Södertälje, Sweden

    Eva-Lena Glämsta & Håkan Andersson

  4. Regulatory Bioanalysis, Global DMPK, Mölndal, Sweden

    Lars B. Nilsson

  5. Discovery Sciences, AstraZeneca R&D, 151 85, Södertälje, Sweden

    Susanne Rosqvist

  6. Global DMPK, Centre of Excellence, Innovative Medicines, AstraZeneca R&D, 151 85, Södertälje, Sweden

    Sandra A. G. Visser

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  1. Petra Ekerot
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Correspondence to Sandra A. G. Visser.

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Ekerot, P., Ferguson, D., Glämsta, EL. et al. Systems Pharmacology Modeling of Drug-Induced Modulation of Thyroid Hormones in Dogs and Translation to Human. Pharm Res 30, 1513–1524 (2013). https://doi.org/10.1007/s11095-013-0989-4

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  • DOI: https://doi.org/10.1007/s11095-013-0989-4

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