Abstract
Background: Levothyroxine (LT4) sodium is a standard treatment for hypothyroidism. Its absorption and bioavailability when taken as a tablet have been shown to be significantly decreased with concomitant food ingestion. Therefore, LT4 formulations are recommended to be taken on an empty stomach, at least 30, ideally 60, minutes before breakfast, potentially affecting adherence to therapy. A novel LT4 solution (Tirosint(®)-SOL) has been shown to result in a faster absorption process than tablets or soft-gel capsule formulations. The objective of this trial was to evaluate the bioavailability of this preparation taken 15 minutes before a high-fat high-calorie meal in comparison with the minimally recommended 30-minute interval. Methods: Thirty-six (33 completers, 24 males and 9 females) healthy volunteers participating in the randomized study took 600 mcg of LT4 oral solution, single doses after a 10-hour fast, 15 or 30 minutes before a high-fat, high-calorie, FDA-approved standardized meal in a controlled research setting. We measured serum total thyroxine using Liquid Chromatography with Tandem Mass Spectrometry at baseline and multiple time points up to 72 hours after LT4 administration. The predefined equivalence boundaries for the extent of exposure reflected by the area under the curve (AUC) were 80-125%. The washout period was at least 35 days. Results: The geometric mean ratios and confidence intervals (CIs) for the baseline-adjusted extent of exposure represented by AUCs truncated at both 48 and 72 hours after dosing (AUC(0-48): 90% [90% CI 86-94]; and AUC(0-72): 92% [90% CI 87-97]) were within the prespecified equivalence boundaries. The baseline-adjusted peak concentration was also clinically similar (C(max): 85% [90% CI 80-90]). The median t(max) was 1.5 hours in each group. The rate of adverse events was similar between groups. Conclusions: We observed no significant difference in the pharmacokinetic properties of a novel LT4 solution administered 15 and 30 minutes before a high-fat high-calorie meal in normal subjects. Further research is needed to evaluate (a) the differences in overall bioavailability at other time points (including immediately premeal) and (b) the real-world effectiveness of this preparation in newly proposed administration conditions to optimize treatment outcomes in hypothyroid patients.