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Thyroid. 2006 Dec;16(12):1279-92.

L-T4 bioequivalence and hormone replacement studies via feedback control simulations.

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1
Biocybernetics Laboratory, Departments of Computer Science, Medicine and Biomedical Engineering UCLA, Los Angeles, California 90095-1596, USA. marisa@cs.ucla.edu

Erratum in

  • Thyroid. 2007 Apr;17(4):378.

Abstract

FDA Guidance for testing bioequivalence of levothyroxine (L-T(4)) preparations has been challenged by several groups, based on multiple issues. The efficacy of single versus combined hormone therapy also is receiving additional scrutiny. To examine these concerns, we developed a new nonlinear feedback system simulation model of whole-body regulation mechanisms involving dynamics of T(3), T(4), TSH, plasma protein binding, extravascular regulatory enzyme systems, and the hypothalamic-pituitary-thyroid axis, all quantified from human data. To address bioequivalence, we explored how to best account for varying and unmeasured endogenous T(4) following dosing with exogenous oral L-T(4) in euthyroid volunteers in required pharmacokinetic (PK) studies, by simulating various dosing scenarios and developing a new and simple correction method. We computed and assessed dosing error effects and baseline corrections using simulator-predicted endogenous T(4) level variations, due to actual closed-loop effects, and compared these with approximate corrections computed directly from PK data. Predicted dose-responses were quite linear, and for constant baseline, 7-day half-life, and our new formula-correction methods, we established some bounds on bioequivalent dosages. Simulated replacement after thyroidectomy required 141 microg L-T(4) only to normalize T(3) tissue levels and 162 microg L-T(4) to normalize plasma T(3) levels. A combined dose of approximately 103 microg L-T(4) plus approximately 6 microg T(3) ( approximately 18:1 ratio) was needed to normalize both plasma T(3) and T(4) and average tissue T(3) levels. However, simulated average tissue T(3) levels were normalized with standard L-T(4)-only therapy, and plasma T(3) levels were still within the normal range. We suggest a simple and more accurate correction for endogenous T(4) in PK studies. Current standard L-T(4)-only treatment is supported for routine replacement needs.

PMID:
17199439
DOI:
10.1089/thy.2006.0144
[Indexed for MEDLINE]
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