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Levothyroxine dosage and the limitations of current bioequivalence standards

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 474–475 (2006)Cite this article

Precision in the dosing of levothyroxine (LT4) products is guided by sensitive TSH measurements, and is essential to optimize therapeutic outcomes and assure patient safety. FDA regulation of LT4 formulations aims to provide consistent drug content and bioavailability of the individual products approved for distribution in the US.1,2 What is unclear at this point, however, is whether true generic interchangeability among approved products has been achieved.

Once absorbed, orally dosed LT4 exerts physiologic effects on metabolism, and a dynamic feedback effect on the hypothalamic–pituitary axis.3 In healthy individuals, the resultant modulation of the production and clearance of endogenous T4 probably affects total circulating hormone levels. As LT4 is converted to T3 for therapeutic effect, measuring the concentration of the active ingredient (T3) at the site of action—as is the intent of bioequivalence determinations—becomes impractical. In this situation, the quantification of total T4 levels in the blood serves as the FDA-designated pharmacokinetic measure of choice.4

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References

  1. Hennessey JV (2003) Levothyroxine a new drug? Since when? How could that be? Thyroid 13: 279–282

    Article  Google Scholar 

  2. US Department of Health and Human Services, FDA, and Center for Drug Evaluation and Research (2002) Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations [http://www.fda.gov/cder/guidance/4964dft.pdf] (accessed 19 July 2006)

  3. FDA (2005) Itinery for the joint public meeting on equivalence of levothyroxine sodium products [http://www.fda.gov/ohrms/dockets/dockets/05n0137/05n-0137-lst0001.pdf] (accessed 19 July 2006)

  4. FDA (2005) Code of federal regulations, title 21, vol 5, subchapter D, part 320 [http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320&show] (accessed 19 July 2006)

  5. Carr D et al. (1988) Fine adjustment of thyroxine replacement dosage: comparison of the thyrotropin releasing hormone test using a sensitive thyrotropin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol 28: 325–333

    Article  CAS  Google Scholar 

  6. Henderson JD and Esham RH (2001) Generic drug substitution: issues for problematic drugs. South Med J 94: 16–21

    Article  CAS  Google Scholar 

  7. FDA (2003) Advisory committee for pharmaceutical science 12–13 March 2003 [http://www.fda.gov/ohrms/dockets/ac/03/briefing/3926B1_01_H-FDA-Additional%20Information.doc] (accessed 19 July 2006)

  8. Blakesley VA et al. (2004) Are bioequivalalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable? Thyroid 14: 191–200

    Article  CAS  Google Scholar 

  9. FDA (2006) Drugs@FDA [http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm] (accessed 19 July 2006)

  10. American Association of Clinical Endocrinologists, the Endocrine Society and the American Thyroid Association (2005) Joint position statement on the use and interchangeability of thyroxine products [http://www.thyroid.org/professionals/advocacy/04_12_08_thyroxine.html] (accessed 19 July 2006)

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  1. Associate Professor of Medicine at the Brown Medical School, Rhode Island Hospital, Providence, RI, USA

    James V Hennessey

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  1. James V Hennessey
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Correspondence to James V Hennessey.

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Competing interests

Research support from Novartis and Abbott Laboratories; Speaker honoraria from Abbott Laboratories and Aventis.

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Hennessey, J. Levothyroxine dosage and the limitations of current bioequivalence standards. Nat Rev Endocrinol 2, 474–475 (2006). https://doi.org/10.1038/ncpendmet0273

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