Are Bioequivalence Studies of Levothyroxine Sodium Formulations in Euthyroid Volunteers Reliable?

Abstract

Levothyroxine (LT₄) has a narrow therapeutic index. Consequently, precise standards for assessing the bioequivalence of different LT₄ products are vital. We examined the methodology that the Food and Drug Administration (FDA) recommends for comparing the bioavailability of LT₄ products, as well as three modifications to correct for endogenous, thyroxine (T₄) levels, to determine if the methodology could distinguish LT₄ products that differ by 12.5%, 25%, or 33%. With no baseline correction for the endogenous T₄ pool, differences in administered LT₄ doses that differed by 25%-33% could not be detected (450 μg and 400 μg doses versus 600 μg dose, respectively). The three mathematical correction methods could distinguish the doses that differed by 25% and 33%. None of the correction methods could distinguish dosage strengths that differed by 12.5% (450 μg versus 400 μg). Dose differences within this range are known to result in clinically relevant differences in safety and effectiveness. Methods of analysis of bioequivalence data that do not consider endogenous T₄ concentrations confound accurate quantitation and interpretation of LT₄ bioavailability. As a result, products inappropriately deemed bioequivalent may put patients at risk for iatrogenic hyperthyroidism or hypothyroidism. More precise methods for defining bioequivalence are required in order to ensure that LT₄ products accepted as bioequivalent will perform equivalently in patients without the need for further monitoring and retitration of their dose.