New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Abstract

Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.

Methods: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50 μg, 100 μg, and 200 μg L-T4 tablets, at a total dose of 600 μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (C_max) of thyroxine (T4) in plasma.

Results: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC_0–72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the C_max,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8–1.25): the three dose strengths were dosage form proportional.

Conclusions: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.

Keywords:

• Bioequivalence
• dosage form proportionality
• levothyroxine
• pharmacokinetic trials
• specification

Transparency

Declaration of funding

This study was funded by Merck KGaA, Darmstadt, Germany.

Author contributions: All authors were involved in the concept and design of the study, analysis and interpretation of data, and critical revision of the manuscript. All authors also provided approval for submission of the manuscript and are fully accountable for all aspects of the work.

Declaration of financial/other relationships

U.G.-H. and P.W. have disclosed that they are employees of Merck KGaA. W.U. has disclosed that he is a former employee of Merck KGaA. G.J.K. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO Peer Reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Assistance with writing was provided by Jennifer Mayes PhD of Fishawack Communications GmbH, and funded by Merck KGaA, Darmstadt, Germany.