l-Thyroxine in an Oral Liquid or Softgel Formulation Ensures More Normal Serum Levels of Free T4 in Patients with Central Hypothyroidism
Open accessAbstract
Context: L-thyroxine therapy of central hypothyroidism (CH) is guided by measurements of serum free thyroxine (FT4), which should be above the midnormal range value (MNRV). In some countries, novel formulations of oral L-thyroxine (liquid or softgel) are available further to the classic tablets. The intestinal absorption of either novel formulation is greater than tablets in patients with primary hypothyroidism. Objective: To evaluate if new oral formulations of L-T4 could be considered optimal in patients with central hypothyroidism who do not reach the FT4 target using tablet L-thyroxine. [Q5 Rev1] Design: Our observation of six patients with isolated CH and serum FT4 below MNRV under stable adequate doses of tablet L-thyroxine (median 1.51 µg/Kg bw/day), prompted us to switch them to liquid (n= 4) or softgel (n=3) L-thyroxine at the same dose, and verify whether FT4 increased above MNRV. A seventh patient with FT4 above MNRV was enrolled because she wanted a “more modern formulation”. Post-switch FT4 was measured at least twice with the same kit as pre-switch FT4. Results: In the first six patients, post-switch FT4 averaged 13.0±1.6 pg/ml compared to 10.4±1.8 pre-switch FT4 (P= 0.00026), with 11/13 (85%) measurements above MNRV compared to 0/20. In the liquid or softgel L-thyroxine group, post-switch FT4 averaged 13.1±1.6 vs 10.6±0.9 pg/ml pre-switch (P=0.0004) or 12.9±2.1 vs 10.3±2.4 (P=0.048) respectively. [Q5 Rev1] In the seventh patient (switched to liquid L-thyroxine), averages were 18.3 vs 15.2 pg/ml, and proportions 4/4 vs 2/2. Conclusion: In CH patients oral liquid or softgel L-thyroxine administered at the same doses as tablet L-thyroxine ensures target serum FT4 levels above MNRV that tablet L-thyroxine may miss. In turn, this performance confirms suggests [Q5 Rev2] the more favorable pharmacokinetics profile of either novel formulation compared with the tablet formulation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Approximately 20% of patients with primary hypothyroidism and approximately 20% or 40% of patients with central hypothyroidism are undertreated, with co-administration of interfering medications being one major cause.
“≈20% of patients with PH (10–13) and ≈20% (14) or 40% (15) of patients with CH are undertreated, co-administration of interfering medications (IM) being one major cause.”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [14]
L-T4 formulations (liquid, softgel) are refractory or much more resistant to interacting medications than tablet L-T4.
“the availability of L-T4 formulations (liquid, softgel) that are refractory or much more resistant to IM than tablet L-T4 (9, 14, 98, 100, 109–114).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [14]
Orally administered liquid and soft-gel LT4 formulations are associated with higher serum FT4 levels and lower TSH levels than tablet formulations, even when the overall LT4 dose level is the same.
“Other reports from both retrospective and prospective observational studies indicate that orally administered liquid and soft-gel formulations of LT4 are associated with higher serum FT4 levels and lower TSH levels than tablet formulations, even when the overall LT4 dose level is the same – perhaps due to the absence of gastric disintegration [ 38 – 44 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [38]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., et al. (2014) · Thyroid® · doi:10.1089/thy.2014.0028 · Cited by 1,928 · see citing works
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567 · see citing works
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053 · see citing works
Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text
(1992) · Annals of Internal Medicine · doi:10.7326/0003-4819-117-6-541_8 · Cited by 302 · see citing works
A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism
Colucci, P., Yue, C. S., Ducharme, M., Benvenga, S., Principal Scientist, L. A. C. I., Principal Scientist, L. A. C. I. A. P. C., President and CEO, L. A. C. I., & Professor of Medicine, D. (2010) · European Endocrinology · doi:10.17925/ee.2013.09.01.40 · Cited by 167 · see citing works
Self-citationVita, R., Saraceno, G., Trimarchi, F., & Benvenga, S. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2684 · Cited by 99 · see citing works
Self-citationThe administration of l -thyroxine as soft gel capsule or liquid solution
Vita, R., Fallahi, P., Antonelli, A., & Benvenga, S. (2014) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2014.918101 · Cited by 93 · see citing works
Self-citationVita, R., Saraceno, G., Trimarchi, F., & Benvenga, S. (2013) · Endocrine · doi:10.1007/s12020-012-9772-2 · Cited by 91 · see citing works
Yue, C., Scarsi, C., & Ducharme, M. P. (2012) · Arzneimittelforschung · doi:10.1055/s-0032-1329951 · Cited by 81 · see citing works
Fallahi, P., Ferrari, S. M., Camastra, S., Politti, U., Ruffilli, I., Vita, R., Navarra, G., Benvenga, S., & Antonelli, A. (2017) · Obesity Surgery · doi:10.1007/s11695-016-2247-4 · Cited by 81 · see citing works
Self-citationCappelli, C., Pirola, I., Daffini, L., Formenti, A., Iacobello, C., Cristiano, A., Gandossi, E., Agabiti Rosei, E., & Castellano, M. (2016) · Thyroid · doi:10.1089/thy.2015.0422 · Cited by 80 · see citing works
When thyroid hormone replacement is ineffective?
Benvenga, S. (2013) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000003 · Cited by 74 · see citing works
Self-citationLiquid and softgel levothyroxine use in clinical practice: state of the art
Virili, C., Trimboli, P., Romanelli, F., & Centanni, M. (2016) · Endocrine · doi:10.1007/s12020-016-1035-1 · Cited by 71 · see citing works
Vita, R., & Benvenga, S. (2014) · Endocrine Practice · doi:10.4158/ep13316.cr · Cited by 60 · see citing works
Self-citationBenvenga, S., Di Bari, F., & Vita, R. (2017) · Endocrine · doi:10.1007/s12020-017-1244-2 · Cited by 51 · see citing works
Self-citationBrancato, D., Scorsone, A., Saura, G., Ferrara, L., Di Noto, A., Aiello, V., Fleres, M., & Provenzano, V. (2014) · Endocrine Practice · doi:10.4158/ep13418.or · Cited by 44 · see citing works
Seng Yue, C., Benvenga, S., Scarsi, C., Loprete, L., & Ducharme, M. (2015) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j36p5m · Cited by 41 · see citing works
Self-citationFallahi, P., Ferrari, S. M., & Antonelli, A. (2016) · Endocrine Practice · doi:10.4158/ep161545.or · Cited by 28 · see citing works
Flagged first, then by citations
1 of the 19 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The diagnosis and management of central hypothyroidism in 2018
Persani, L., Cangiano, B., & Bonomi, M. (2019) · Endocrine Connections · doi:10.1530/ec-18-0515 · Cited by 64 · see citing works
New Formulations of Levothyroxine in the Treatment of Hypothyroidism: Trick or Treat?
Nagy, E. V., Perros, P., Papini, E., Katkó, M., & Hegedűs, L. D. (2020) · Thyroid · doi:10.1089/thy.2020.0515 · Cited by 65 · see citing works
Caron, P., Grunenwald, S., Persani, L., Borson-Chazot, F., Leroy, R., & Duntas, L. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09691-9 · Cited by 53 · see citing works
Novel thyroxine formulations: a further step toward precision medicine
Virili, C., Trimboli, P., & Centanni, M. (2019) · Endocrine · doi:10.1007/s12020-019-02049-x · Cited by 41 · see citing works
L-T4 Therapy in Enteric Malabsorptive Disorders
Fallahi, P., Ferrari, S. M., Elia, G., Ragusa, F., Paparo, S. R., & Antonelli, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.626371 · Cited by 23 · see citing works
Trimboli, P., Virili, C., Centanni, M., & Giovanella, L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00118 · Cited by 21 · see citing works
Bornikowska, K., Gietka-Czernel, M., Raczkiewicz, D., Glinicki, P., & Zgliczyński, W. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10225233 · Cited by 17 · see citing works
Benvenga, S. (2019) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2019.100204 · Cited by 17 · see citing works
Self-citationL-T4 therapy in the presence of pharmacological interferents
Benvenga, S. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.607446 · Cited by 13 · see citing works
“However, ≈20% of patients with PH (10–13) and ≈20% (14) or 40% (15) of patients with CH are undertreated, co-administration of interfering medications (IM) being one major cause.”
BackgroundSelf-citationGietka-Czernel, M., Hubalewska-Dydejczyk, A., Kos-Kudła, B., Lewiński, A., Ruchała, M., Syrenicz, A., & Zgliczyński, W. (2020) · Endokrynologia Polska · doi:10.5603/ep.a2020.0065 · Cited by 13 · see citing works
Stagi, S., Municchi, G., Ferrari, M., & Wasniewska, M. G. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.859487 · Cited by 14 · see citing works
Interactions between hypothalamic pituitary thyroid axis and other pituitary dysfunctions
Feldt-Rasmussen, U., Klose, M., & Benvenga, S. (2018) · Endocrine · doi:10.1007/s12020-018-1738-6 · Cited by 12 · see citing works
Self-citationTrimboli, P., & Mouly, S. J. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11123479 · Cited by 11 · see citing works
Markantes, G. Κ., Dimitropoulos, K., Mamali, I., Tseti, I. K., Sakellaropoulos, G. C., Markou, K. B., & Michalaki, M. A. (2020) · European Thyroid Journal · doi:10.1159/000508216 · Cited by 8 · see citing works
Cappelli, C., Pirola, I., & Castellano, M. (2020) · Case Reports in Endocrinology · doi:10.1155/2020/8858887 · Cited by 5 · see citing works
Almukainzi, M., Alqahtani, R. A., Alanazi, R., Alamri, R., & Alayed, H. (2023) · Obesity Surgery · doi:10.1007/s11695-023-06970-z · Cited by 4 · see citing works
Drug forms of levothyroxine. Is there room for innovation in hypothyroidism treatment?
Kolpakova, E. A., Voznesenskaya, А. А., Викторовна, Ф. Н., & Troshina, E. A. (2023) · Clinical and experimental thyroidology · doi:10.14341/ket12759 · Cited by 1 · see citing works
An, P., Cao, M., Tang, W., Wang, Q., Ji, Q., Wang, Y., Feng, Z., Zhang, D., & Chen, X. (2026) · Animal Reproduction Science · doi:10.1016/j.anireprosci.2026.108230 · Cited by 1 · see citing works
- Authors
- Benvenga, S., Capodicasa, G., & Perelli, S.
- Affiliations
- University of Messina (IT)
- Corresponding author
- Perelli, Sarah
- ORCID
- Benvenga, Salvatore
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2017-11-20
- Volume
- 8
- Pages
- 321-321
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC5701926
- OpenAlex
- W2770853539
- Cited by
- 18
- References
- 19
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 2
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- central hypothyroidism, levothyroxine, liquid formulation, free thyroxine, oral drug absorption, thyroid hormone replacement, dose adjustment, treatment response variability, quality of life, patient satisfaction, medication adherence
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
