Extensions, Validation, and Clinical Applications of a Feedback Control System Simulator of the Hypothalamo-Pituitary-Thyroid Axis

Eisenberg, Marisa C.; Samuels, Mary H.; DiStefano, Joseph J.

doi:10.1089/thy.2007.0388

Cited by 56 publications

(64 citation statements)

References 43 publications

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“…The model has two major components: the brain submodels (26), and the TH secretion and distribution and elimination (D&E) submodels (15), updated in (26). The brain submodels incorporate circadian TSH secretion regulated by T 3 and T 4 in brain, and a simple one-compartment TSH degradation model.…”

Section: Simulation Modelmentioning

confidence: 99%

“…An explicit gut submodel provides for oral L-T 4 inputs and adjustment of gut absorption rates. All are detailed in (26). …”

Section: Simulation Modelmentioning

confidence: 99%

“…We address three issues in assessment of bioequivalence here, using our second-generation simulation model of human thyroid hormone (TH) regulation, recently quantified and validated against data that span a wide range of normal and abnormal thyroid system function (26). In brief, the nonlinear dynamic feedback control system (FBCS) model includes thyroid secretion, TSH secretion with feedback regulation by T 3 and T 4 , distribution, metabolism, and elimination of TH in and from all tissue pools-including T 4 to T 3 conversion, plasma protein binding effects, and a gut absorption submodel, for exogenous TH dosing.…”

Section: Introductionmentioning

confidence: 99%

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TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

Eisenberg¹,

DiStefano²

2009

Thyroid

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Background: FDA Guidance for pharmacokinetic (PK) testing of levothyroxine (L-T 4 ) for interbrand bioequivalence has evolved recently. Concerns remain about efficacy and safety of the current protocol, based on PK analysis following supraphysiological L-T 4 dosing in euthyroid volunteers, and recent recalls due to intrabrand manufacturing problems also suggest need for further refinement. We examine these interrelated issues quantitatively, using simulated what-if scenarios testing efficacy of a TSH-based protocol and tablet stability and absorption, to enhance precision of L-T 4 bioequivalence methods. Methods: We use an updated simulation model of human thyroid hormone regulation quantified and validated from data that span a wide range of normal and abnormal thyroid system function. Bioequivalence: We explored a TSH-based protocol, using normal replacement dosing in simulated thyroidectomized patients, switching brands after 8 weeks of full replacement dosing. We simulated effects of tablet potency differences and intestinal absorption differences on predicted plasma TSH, T 4 , and triiodothyronine (T 3 ) dynamics. Stability: We simulated effects of potency decay and lot-by-lot differences in realistic scenarios, using actual tablet potency data spanning 2 years, comparing the recently reduced 95-105% FDA-approved potency range with the original 90-110% range. Results: A simulated decrease as small as 10-15% in L-T 4 or its absorption generated TSH concentrations outside the bioequivalence target range (0.5-2.5 mU=L TSH), whereas T 3 and T 4 plasma levels were maintained normal. For a 25% reduction, steady-state TSH changed 300% (from 1.5 to 6 mU=L) compared with <25% for both T 4 and T 3 (both within their reference ranges). Stability: TSH, T 4 , and T 3 remained within normal ranges for most potency decay scenarios, but tablets of the same dose strength and brand were not bioequivalent between lots and between fresh and near-expired tablets. Conclusions: A pharmacodynamic TSH-measurement bioequivalence protocol, using normal L-T 4 replacement dosing in athyreotic volunteers, is likely to be more sensitive and safer than current FDA Guidance based on T 4 PK. The tightened 95-105% allowable potency range for L-T 4 tablets is a significant improvement, but otherwise acceptable potency differences (whether due to potency decay or lot-by-lot inconsistencies) may be problematic for some patients, for example, those undergoing high-dose L-T 4 therapy for cancer.

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Section: Simulation Modelmentioning

confidence: 99%

“…An explicit gut submodel provides for oral L-T 4 inputs and adjustment of gut absorption rates. All are detailed in (26). …”

Section: Simulation Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

Eisenberg¹,

DiStefano²

2009

Thyroid

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“…Although the mechanism is unknown, diminished circadian rhythms also are observed in central hypothyroidism. Indeed, they are speculated to be one cause of the disease (6,7,9), although multiple factors may contribute to central hypothyroidism, including mutations in the thyrotropin releasing hormone (TRH) or TSH gene and improper glycosylation, among others (10-12).We address these issues here by augmenting and extending a human TH feedback control system simulation model (13,14) into the extreme hypothyroid range, supported by human data in this range. We examine whether saturation of TSH secretion, previously suggested in extreme primary hypothyroidism (6), might explain diminished circadian rhythms in both disorders.…”

mentioning

confidence: 99%

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

Eisenberg

Santini

Marsili

et al. 2010

Thyroid

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Background: Thyrotropin (TSH) changes in extreme primary hypothyroidism include increased secretion, slowed degradation, and diminished or absent TSH circadian rhythms. Diminished rhythms are also observed in central hypothyroid patients and have been speculated to be a cause of central hypothyroidism. We examined whether TSH secretion saturation, previously suggested in extreme primary hypothyroidism, might explain diminished circadian rhythms in both disorders. Methods: We augmented and extended the range of our published feedback control system model to reflect nonlinear changes in extreme primary hypothyroidism, including putative TSH secretion saturation, and quantified and validated it using multiple clinical datasets ranging from euthyroid to extreme hypothyroid (postthyroidectomy). We simulated central hypothyroidism by reducing overall TSH secretion and also simulated normal TSH secretion without circadian oscillation, maintaining plasma TSH at constant normal levels. We also utilized the validated model to explore thyroid hormone withdrawal protocols used to prepare remnant ablation in thyroid cancer patients postthyroidectomy. Results: Both central and extreme primary hypothyroidism simulations yielded low thyroid hormone levels and reduced circadian rhythms, with simulated daytime TSH levels low-to-normal for central hypothyroidism and increased in primary hypothyroidism. Simulated plasma TSH showed a rapid rise immediately following triiodothyronine (T 3 ) withdrawal postthyroidectomy, compared with a slower rise after thyroxine withdrawal or postthyroidectomy without replacement. Conclusions: Diminished circadian rhythms in central and extreme primary hypothyroidism can both be explained by pituitary TSH secretion reaching maximum capacity. In simulated remnant ablation protocols using the extended model, TSH shows a more rapid rise after T 3 withdrawal than after thyroxine withdrawal postthyroidectomy, supporting the use of replacement with T 3 prior to 131 I treatment. IntroductionT wo well-known hallmarks of normal thyrotropin (TSH) dynamics are high sensitivity to small changes in circulating thyroid hormone (TH) and circadian oscillations. TSH changes in extreme primary hypothyroidism include increased TSH secretion, slowed degradation (1), effects of compensatory changes in deiodinase activity, particularly type 2 deiodinase (D2) upregulation in brain (2-5), and diminished or absent circadian rhythms (6)(7)(8). Although the mechanism is unknown, diminished circadian rhythms also are observed in central hypothyroidism. Indeed, they are speculated to be one cause of the disease (6,7,9), although multiple factors may contribute to central hypothyroidism, including mutations in the thyrotropin releasing hormone (TRH) or TSH gene and improper glycosylation, among others (10-12).We address these issues here by augmenting and extending a human TH feedback control system simulation model (13,14) into the extreme hypothyroid range, supported by human data in this range. We examine whether saturation o...

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“…The role of thyroid hormones are needed for the regulation of metabolism of all the cells in one or another way in the body. When there is not sufficient thyroid hormone (hypothyroidism) the body's metabolism reduces and this is determined by variations in the various tissues [4]. Thyroxine is the major product of the thyroid gland and much of it is later deiodinated in extrathyroidal tissue to form T3.…”

Section: Introductionmentioning

confidence: 99%

A Method to Simulate Treatment of Thyroid Problems in the Human Body

Chawla¹,

Pal²

2014

IJCA

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This is an effort to simulate the concept of treatment of different types of Thyroidism after determining the TSH, T3 and T4 levels in the human body. The target is to determine the effective dose of Thyroxine to be provided to the patient so that normal level of the same can be maintained in the human body. It interacts with every organ system and plays a crucial role in metabolism [1], but there is no software technique to bypass the doctors for the treatment of Thyroid malfunctioning. The Analog devices like operational amplifiers have features identical to the arithmetic operations. Primarily, the voltages in the high-gain dc amplifiers can be reduced to an average to these three variables and the operational amplifiers can do the arithmetic operations on the voltages, the accuracy of measuring voltage may be circumscribed to limited point. A Digital circuit has been implemented to determine the dosage required by the patients using the best market products. The simulation has been done using CircuitMaker ( Student version).

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Extensions, Validation, and Clinical Applications of a Feedback Control System Simulator of the Hypothalamo-Pituitary-Thyroid Axis

Cited by 56 publications

References 43 publications

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

A Method to Simulate Treatment of Thyroid Problems in the Human Body

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Extensions, Validation, and Clinical Applications of a Feedback Control System Simulator of the Hypothalamo-Pituitary-Thyroid Axis

Cited by 56 publications

References 43 publications

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4Bioequivalence

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4Bioequivalence

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

A Method to Simulate Treatment of Thyroid Problems in the Human Body

Contact Info

Product

Resources

About

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence