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Cited by 43Thyroid Disorders and TreatmentsPharmaceutical studies and practicesAnalytical Methods in Pharmaceuticals

New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials

Gottwald-Hostalek, Ulrike, Uhl, Wolfgang, Wolna, Peter, Kahaly, George J.·2017·Current Medical Research and Opinion
DOI 10.1080/03007995.2016.1246434
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Abstract

Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.Methods: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50 μg, 100 μg, and 200 μg L-T4 tablets, at a total dose of 600 μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (Cmax) of thyroxine (T4) in plasma.Results: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC0–72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the Cmax,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8–1.25): the three dose strengths were dosage form proportional.Conclusions: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.

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  • A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches, and the results are controversial.

    “A number of studies have evaluated the interchangeability of LT4 among manufacturers, brands, or batches (106–108), and the results are controversial.”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [106]

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Authors
Gottwald-Hostalek, U., Uhl, W., Wolna, P., & Kahaly, G. J.
Affiliations
  • Merck KGaA, Darmstadt, Germany;
  • Former employee of Merck KGaA;
  • Merck KGaA, Darmstadt (Germany) (DE)
  • University Medical Center of the Johannes Gutenberg University Mainz (DE)
ORCID
Kahaly, George J.
Venue
Current Medical Research and Opinion
Publisher
Informa UK Limited
Published
2016-10-21
Volume
33
Issue
2
Pages
169-174
ISSN
  • 0300-7995 (ISSN-L)
  • 1473-4877
DOI
10.1080/03007995.2016.1246434
OpenAlex
W2529032989
Cited by
43
References
25
Citations by year
2024: 4 · 2023: 4 · 2022: 11 · 2021: 3 · 2020: 3 · 2019: 14 · 2018: 4
FWCI
6.03
Type
journal article
Language
en
Open access
closed
Locations
  • Current Medical Research and Opinion (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Keywords
levothyroxine, levothyroxine sodium, bioequivalence, shelf life, dose adjustment, thyroid hormone replacement, crossover trial, area under the curve, maximum concentration
MeSH terms
Adult, Chemistry, Pharmaceutical, Female, Humans, Male, Tablets, Therapeutic Equivalency, Thyroxine, Cross-Over Studies, Area Under Curve

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