Bioequivalence of two levothyroxine tablet formulations without and with mathematical adjustment for basal thyroxine levels in healthy Argentinian volunteers: A single-dose, randomized, open-label, crossover study

Abstract Background: Levothyroxine has a narrow therapeutic index; therefore, precise and accurate assessment of the bioequivalence of different levothyroxine products is critical. Bioavailability estimates of levothyroxine formulations might be affected by baseline concentrations of the hormone. Objectives: The aim of this study was to assess the bioequivalence of 100 µg of a test (T4 Montpellier® 100, Química Montpellier S.A., Buenos Aires, Argentina) and reference (Synthroid® , Abbott Laboratories, Abbott Park, Illinois) formulation of levothyroxine. We also compared 2 methods of levothyroxine measurements: without and with baseline correction for endogenous levothyroxine. Methods: This randomized, open-label, 2-sequence, crossover study with a 65-day washout period was carried out in healthy, white, euthyroid volunteers following a single dose of sodium levothyroxine 600 µg. Blood samples were collected at 30 and 15 minutes prior to administration, and 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 48 hours to determine thyroxine; serum thyrotropin (TSH) concentrations were determined 30 minutes before administration and 48 hours after administration. Serum concentrations of thyroxine were determined through radioimmunoassay and serum TSH concentrations were determined by a validated 2-site immunoradiometric assay. The formulations are considered to be equivalent if the 90% CI ratios for Cmax and AUC0-last are within 80% to 125%, per the US Food and Drug Administration (FDA). Adverse event monitoring was performed throughout the study by assessing clinical parameters (eg, blood pressure, electrocardiogram) and patient reports. Results: A total of 24 volunteers (16 male, 8 female; mean [SD] age, 30.2 [4.6] years [range, 21-40 years]; mean [SD] weight, 71.71 [7.52] kg [range, 58-83 kg]) were included in the study. Without adjustment for baseline levels of endogenous levothyroxine, geometric mean Cmax for the test and reference formulations were 8.92 and 9.39 µg/dL, respectively; AUC0-last values were 368.40 and 383.37 µg/mL · h-1 . The 90% CI of the geometric mean for the percent ratios (test: reference) of Cmax and AUC0-last were 95.1% (90% CI, 91.9–98.3) and 96.1% (90% CI, 94.0–98.2), respectively. With adjustment for baseline levels of endogenous levothyroxine, the geometric mean Cmax for the test and reference formulations were 3.16 and 3.39 µg/dL, respectively; AUC0-last values were 88.33 and 95.60 µg/mL · h-1 . Despite performing th