Timing of liquid LT4 intake doesn’t impact bioavailability

Bioavailability studies presented at ENDO 2022 showed that patients with hypothyroidism can safely take the liquid formulations of levothyroxine (LT4) 15 or 30 minutes before meals, without having to worry about food effect on bioavailability.

LT4 is a life-long medication for hypothyroidism that is taken daily. The drawback is that absorption and bioavailability of LT4 decrease with concomitant food ingestion. In one study, co-administration of LT4 tablets with a high-fat high-calorie meal significantly reduced T4 C_max by 40–49 percent and AUC_0–48 by 38–40 percent with respect to fasting conditions. [Thyroid 2004; 14:876]

For this reason, current guidelines recommend that LT4, in any dosage form, be taken on an empty stomach, 30–60, minutes before breakfast for better absorption. However, this is difficult for most patients to adhere to, compromising therapeutic targets.

In a cross-over study, there was no difference in comparison of an LT4 oral solution whether it is taken with or without a waiting period prior to consuming coffee.

Forty healthy adults were randomly assigned, after a 10-hour overnight fast, to 600 µg Thyquidity with water under fasting conditions or 5 minutes prior to drinking black coffee.

Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including AUC and C_max, were comparable in both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96 percent and 94 percent for C_max and AUC, respectively. The corresponding 90 percent confidence intervals (CI) fell within the 80–125 percent FDA acceptance range for the absence of food effect on bioavailability.

In the second study of 38 healthy adults, the same LT4 formulation was given 10 or 30 minutes prior to the consumption of a high-fat breakfast after a 10-hour fast. Again, mean serum T4 levels were comparable between groups over 48 hours. Similarly, the geometric least squares mean ratios for both AUC and C_max for baseline-adjusted LT4 were 88.7 percent and 85.1 percent, respectively. Again, the corresponding 90 percent CI  fell within the FDA’s range for noninterference, demonstrating a lack of food effect on bioavailability.

While the findings are exciting and encouraging, the researchers said the current FDA-approved label for LT4 stays.

15 vs 30 minutes

In another study, researchers evaluated the bioavailability of another LT4 solution (Tirosint-SOL) taken 15 minutes before a high-fat high-calorie meal compared with the minimally recommended 30-minute interval. [Thyroid 2022;doi.org/10.1089/thy.2021.0604]

Participants included 36 healthy volunteers randomized to a single 600-µg dose of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles, measured using Liquid Chromatography with Tandem Mass Spectrometry at baseline and at multiple timepoints up to 72 hours post-LT4 administration, were similar for both the 15- and 30-minute waits, with similar AUCs.

Geometric mean ratios for AUCs at 48 and 72 hours were 90 percent and 92 percent, respectively. The 90 percent confidence intervals fell within the 80–125 percent FDA boundaries, suggesting similar exposures whether LT4 was taken 15 or 30 minutes before a meal.

“We observed no significant difference in the pharmacokinetic properties of this novel LT4 solution administered 15 and 30 minutes before a high-fat high-calorie meal in normal subjects,” said senior author Dr Francesco Celi from the Virginia Commonwealth University in Richmond, Virginia, US.

“There is an interest in providing more opportunities for patients and improving adherence to medication. Whatever makes life a bit easier for patients and results in a more predictable response to treatment means [that] down the road there will be fewer visits to the doctor to make adjustments, ” he added.

Celi however cautioned that the studies were only done in the short term and were not conducted in real-life settings. Further research is warranted also to evaluate the differences in LT4 bioavailability at other time points.