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The AAPS Journal

, Volume 7, Issue 1, pp E42–E46 | Cite as

Current methodology to assess bioequivalence of levothyroxine sodium products is inadequate

  • Vicky A. BlakesleyEmail author
Article

Abstract

Levothyroxine sodium is a drug with a narrow therapeutic index for which an individual patient must have his or her dose carefully titrated to achieve the necessary therapeutic effect. In addition, exogenous levothyroxine cannot be distinguished from the endogenously produced hormone. Since 2004, generic formulations have been approved for the most frequently prescribed brands of levothyroxine sodium. This review examines the methodology and statistical acceptance criteria and summarizes findings of a previously published relative bioavailability study that brings into question the use of standard criteria to assess bioequivalence of levothyroxine sodium. The key findings reviewed were the following: (1) in the absence of baseline correction for endogenous T4 levels, products that differed by as much as 25% to 33% would be declared bioequivalent; (2) the use of baseline correction reduced the likelihood of declaring products bioequivalent when they actually differed by 25% to 33%; (3) even with baseline correction, products that differed by 12.5% would be declared bioequivalent; and (4) there was evidence of significant carryover from one dosing period to the next even with washout periods of up to 53 days. In conclusion, the current recommended methodology in the United States to assess bioequivalence for levothyroxine sodium products is inadequate to differentiate products that differ by 12.5%, a clinically relevant difference. Recommendations are made for modifications to the criteria that could improve the likelihood that products that differ by a clinically significant amount in their bioavailability would not be accepted as bioequivalent.

Keywords

Levothyroxine Baseline Correction Relative Bioavailability AAPS Journal Dose Period 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  1. 1.Global Pharmaceutical Research and DevelopmentAbbott LaboratoriesAbbott Park

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