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 the adjustment, the 90% CI of the geometric mean for Cmax and AUC0-last test:reference ratios were 93.1% (90% CI, 84.9–102.2) and 92.4% (90% CI, 85.2–100.2), respectively. No significant between-group differences were found with regard to pharmacokinetic parameters. No adverse events were observed or reported.Conclusion: The results of this study suggest that the test formulation was bioequivalent to the reference formulation of levothyroxine in these healthy volunteers, according to the US FDA definition of bioequivalence. This was supported by the analysis of concentration-time profiles without and with correction for basal endogenous levothyroxine.