Absorption of Levothyroxine: What Has the New Formulation of LT4-Containing Medicinal Products Brought?
Lifelong use of levothyroxine (LT4) is the cornerstone of hypothyroidism treatment. The narrow therapeutic range of LT4 places increased emphasis on accurate dosing and appropriate titration, making the introduction of new LT4 formulations with more precise active ingredient dosing and higher levels of bioequivalence a pathway to facilitate LT4 titration and improve patient adherence.
Absorption of Levothyroxine
The bioavailability of LT4 after oral administration is about 70%, with the drug being absorbed mainly in the ileum and jejunum. In patients with hypothyroidism, the maximum plasma concentration (cmax) is reached approximately after 3 hours. The absorption and absolute bioavailability of LT4 may be reduced in pregnant women, in certain intestinal diseases (celiac disease, chronic inflammation of the small intestine), after bariatric surgery or resection of the small intestine, and also in the case of concomitant use of drugs, dietary supplements, food, and beverages. Particularly risky are:
- Proteins from macronutrients (especially soy protein has been studied)
- Beverages such as tea, coffee, and milk (including plant-based alternatives)
- Dietary supplements containing metal ions (calcium, iron, magnesium supplements, multivitamin, and multimineral preparations)
- Medications such as laxatives, antacids, proton pump inhibitors, and sevelamer (a drug used to treat hyperphosphatemia)
Therefore, it is recommended to take LT4 on an empty stomach, i.e., 30 minutes before breakfast or 3 hours after the last evening meal. A study with 90 participants demonstrated that evening administration is associated with higher absorption rates and a more significant decrease in TSH levels compared to the same dose taken in the morning. This is why morning administration of LT4 remains recommended.
Narrow Therapeutic Range
In patients with hypothyroidism, even small deviations in the LT4 dose are associated with significant deviations in thyroid function. Consequently, regulatory authorities classified LT4 among drugs with a narrow therapeutic range years ago. LT4 products are therefore subject to stricter regulations than other drugs, primarily in terms of the accuracy and stability of the active ingredient amount contained in each tablet throughout the product's shelf life. As a result, the composition of excipients in some LT4 products has been altered to significantly slow the degradation of LT4 in the dosage form.
One possible formulation change is the removal of lactose, primarily to increase the stability of LT4 in such a formulated product, rather than in response to adverse effects in lactose-intolerant patients. Generally, the amount of lactose in tablets is low, and thus the likelihood of causing problems in sensitive individuals is also low.
Bioequivalence Study of the New Formulation
When changing the excipients of registered products, the marketing authorization holder must demonstrate that the new composition does not significantly affect drug absorption. Bioequivalence for cmax and the area under the plasma drug concentration curve (AUC) parameters is thus demonstrated. Based on the values measured in a pharmacokinetic clinical study, the average values of these parameters are calculated and compared for the new and previous compositions. For drugs with a narrow therapeutic range, the 90% confidence interval for this ratio must reach 90–111.1% (and for some LT4 products, the manufacturer guarantees an even narrower range: 95–105%), whereas for other drugs, it is 85–125%.
The study comparing the new and original LT4 formulations involved 216 healthy (euthyroid) volunteers. The average values of the measured parameters were very similar, with the ratio of the new to the previous composition being 99.3% for AUC and 101.7% for cmax. The confidence intervals for both ratios met the above condition, thus demonstrating that the new formulation is fully bioequivalent to the original product composition.
Equivalent Exposure with Tablets of Different Strengths
A 2019 clinical study also demonstrated equivalent exposure (cmax and AUC) after administration of 600 µg LT4 using the new formulation tablets of 3 different strengths – low (12× 50 µg), medium (6× 100 µg), and high (3× 200 µg). The study involved 42 healthy volunteers, and the achieved average values of AUC and cmax did not significantly differ depending on the tablet strength administered.
Conclusion
The new formulation of the LT4-containing medicinal product is more stable and ensures more reliable and accurate dosing. This is advantageous both for already stabilized therapy and when dose titration is needed, whether at the start of treatment or when the patient's condition changes. The indicated LT4 dose can be supplemented from any combination of tablet strengths with the new composition.
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Sources:
1. Lipp H.-P. Administration and pharmacokinetics of levothyroxine. In: Lipp H.-P., Kahaly G. (eds.): 70 Years of Levothyroxine. Springer, Cham, 2021, doi: 10.1007/978-3-030-63277-9_2
2. Lipp H.-P., Hostalek U. A new formulation of levothyroxine engineered to meet new specification standards. Curr Med Res Opin 2019; 35 (1): 147–150, doi: 10.1080/03007995.2018.1545635.
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