Levothyroxine Bioequivalence Study and Its Narrow Therapeutic Index: Comparative Bioavailability Results Between Two Formulations Available in Latin America

Abstract

Introduction: The history of levothyroxine has been linked to advances in the treatment of thyroid disease and to date it is the standard therapy for the treatment of hypothyroidism. Bioequivalence studies are the most widely used method to demonstrate interchangeability, although controversy persists regarding the best design for this molecule declared as a narrow therapeutic index product in many countries. This study aimed to evaluate the pharmacokinetic profile of two formulations of levothyroxine to determine bioequivalence between them. Methods: This two-period, randomized, crossover, blind study was conducted in 80 healthy volunteers, of both sexes, using a single levothyroxine dose of 600 μg with a washout period of 42 days. Blood sampling was performed at − 30 min, − 15 min, and 0 h pre-dose and 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, and 48 h post-dose. Results: A total of 78 subjects successfully completed both periods. There were no serious adverse events during the study and both formulations were well tolerated. Baseline correction of serum levothyroxine concentrations was performed before statistical analysis. The mean maximum plasma concentration of the test product (Levotiroxina MK®) was 57.49 ng/mL while for the reference product it reached 59.32 ng/mL. Importantly, both test and reference formulations reached maximum concentrations in plasma at about the same time. The areas under the pharmacokinetic curves with the test product showed AUC0−t of 1407.1 ng h/mL and the reference product 1394.3 ng h/mL. The bioequivalence statistical analysis showed that the 90% confidence interval (CI90%) of the ratio of test over reference formulation was within the bioequivalence margins of 90–111%. For Cmax, the test/reference ratio was 96.2% with CI90% of 91.6–100.9%, and for AUC0−t the test/reference ratio was 99.9 with CI90% of 93.3–107.0%. Conclusions: Both formulations have the same pharmacokinetic profile and are bioequivalent in the narrow therapeutic index required by some health authorities.