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Cited by 43Thyroid Disorders and TreatmentsStatistical Methods in Clinical TrialsPharmaceutical studies and practices

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T 4 Bioequivalence

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Eisenberg, Marisa, Distefano, Joseph J.·2009·Thyroid
DOI 10.1089/thy.2008.0148PMC PMC2858298
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Abstract

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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  • Models based on the UCLA platform delivered an improved baseline correction method that is less prone to interference from functional feedback.

    “Models based on the UCLA platform delivered an improved baseline correction method that is less prone to this kind of interference (27, 28).”

    From Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research (2016) · cites this paper as [27]

    The introduction says an earlier simulation model supported baseline subtraction in FDA testing, and the Methods describe a TSH-based simulation in thyroidectomized patients with no endogenous T4 pool to confound measurements. The paper does not say its UCLA models delivered an improved baseline-correction method or establish that such a method is less prone to feedback interference. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Simulation studies support the use of TSH-based protocols for judging bioequivalence, rather than using pharmacokinetic studies.

    “Simulation studies also support the use of TSH-based protocols for judging bioequivalence, rather than using pharmacokinetic studies (102).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [102]

  • A simulation study in which either LT4 tablet potency or absorption were varied showed that altered absorption could result in achievement of different TSH values (102).

    “A simulation study in which either LT4 tablet potency or absorption were varied showed that altered absorption could result in achievement of different TSH values (102).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [102]

  • A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches, and the results are controversial.

    “A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches (106–108), and the results are controversial.”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [108]

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Research works printed but not linked: 4

  1. [14]Food, Drug Administration. Advisory Committee for Pharmaceutical Science, Record of Proceedings. 2003. http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3926T2.pdf. [Jan 8;2006 ]. http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3926T2.pdf
  2. [16]Food and Drug Administration. Public Meeting for Levothyroxine Sodium Therapeutic Equivalence. Washington, DC: 2005. May 23, 2005. [Jan;2008 ]. [Google Scholar]
  3. [17]Food, Drug Administration. Advisory Committee for Pharmaceutical Science, Record of Proceedings. 2006. http://www.fda.gov/ohrms/dockets/ac/cder06.html#PharmScience. [Apr 26;2007 ]. http://www.fda.gov/ohrms/dockets/ac/cder06.html#PharmScience
  4. [29]Hennessey JV. Sherman S. Personal communication by e-mail. 2007 Apr 9; April 26, 2007. [Google Scholar]

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Related

Authors
Eisenberg, M., & Distefano, J. J.
Affiliations
University of California, Los Angeles (US)
ORCID
Eisenberg, Marisa
Venue
Thyroid
Publisher
SAGE Publications
Published
2009-02
Volume
19
Issue
2
Pages
103-110
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/thy.2008.0148
PMC
PMC2858298
OpenAlex
W2056215471
Cited by
43
References
23
Citations by year
2026: 1 · 2025: 1 · 2024: 3 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 5
FWCI
2.18
Type
journal article
Language
en
Open access
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Thyroid (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Directorate for Biological Sciences
  • National Institute of General Medical Sciences (T32GM008185)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords
levothyroxine, bioequivalence, TSH stimulation test, tablet stability, intestinal absorption, thyroid hormone regulation, triiodothyronine, thyroidectomy, pharmacokinetics, pharmacodynamics, FDA guidance, lot-to-lot variation, thyroid hormone replacement, computer simulation
MeSH terms
Computer Simulation, Drug Stability, Humans, Intestinal Absorption, Tablets, Therapeutic Equivalency, Thyrotropin, Thyroxine, Triiodothyronine

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