Skip to main content
SpringerLink
Log in

Timing of breakfast does not influence therapeutic efficacy of liquid levothyroxine formulation

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Oral levothyroxine (L-T4) is the mainstay of hypothyroidism treatment. Many factors may influence its absorption, including the timing of administration. Objective of the study is to demonstrate the therapeutic equivalence of administering liquid L-T4 with breakfast or 10 min before breakfast. This was a pilot study conducted with a crossover design AB/BA where A stays for L-T4 with breakfast and B for L-T4 10 min before breakfast. A post hoc analysis was conducted to compare L-T4 administered at breakfast or 10 min before breakfast with L-T4 administered 30 min before breakfast. Sixty-one hypothyroid patients were enrolled and assigned to one of the two treatment sequences. All patients were evaluated for TSH levels at the end of each period. Fifty-nine patients completed the study. The mean thyrotropin concentration was 1.52 ± 0.73 µU/ml when L-T4 was administered with breakfast and 1.46 ± 0.81 µU/ml when it was taken 10 min before breakfast, without clinically and statistically significant differences (P = 0.59), regardless of treatment sequence and period. The mean thyrotropin concentration was 1.54 ± 0.9 µU/ml when L-T4 was administered at 0–10 min intervals before breakfast and 1.25 ± 0.7 µU/ml when it was taken 30 min before breakfast (ratio = 1.23, within our definition of equivalence set at 0.8–1.25). There is therapeutic equivalence between liquid L-T4 administration at breakfast or 10 min before breakfast. We can also hypothesize that there are no clinically relevant differences between liquid L-T4 administration 30 min before breakfast or at shorter intervals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. M. Centanni, A. Franchi, M.G. Santaguida, C. Virili, S. Nardo, L. Gargano, Oral thyroxine treatment: towards an individually tailored dose. Recenti Prog. Med. 98, 445–451 (2007)

    PubMed  Google Scholar 

  2. R. Vita, P. Fallahi, A. Antonelli, S. Benvenga, The administration of L-thyroxine as soft gel capsule or liquid solution. Expert Opin. Drug Deliv. 11, 1103–1111 (2014)

    Article  CAS  PubMed  Google Scholar 

  3. L.H. Fish, H.L. Schwartz, J. Cavanaugh, M.W. Steffes, J.P. Bantle, J.H. Oppenheimer, Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N. Engl. J. Med. 316, 764–770 (1987)

    Article  CAS  PubMed  Google Scholar 

  4. M.T. Hays, Absorption of oral thyroxine in man. J. Clin. Endocrinol. Metab. 28, 749–756 (1968)

    Article  CAS  PubMed  Google Scholar 

  5. K.W. Wenzel, H.E. Kirschsieper, Aspects of the absorption of oral L-thyroxine in normal man. Metabolism. 26, 1–8 (1977)

    Article  CAS  PubMed  Google Scholar 

  6. M.T. Hays, Localization of human thyroxine absorption. Thyroid. 1, 241–248 (1991)

    Article  CAS  PubMed  Google Scholar 

  7. M. Centanni, Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. Endocrine 43, 8–9 (2013)

    Article  CAS  PubMed  Google Scholar 

  8. L. Liwanpo, J.M. Hershman, Conditions and drugs interfering with thyroxine absorption. Best Pract. Res. Clin. Endocrinol. Metab. 23, 781–792 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. M.I. Surks, R. Sievert, Drugs and thyroid function. N. Engl. J. Med. 333, 1688–1694 (1995)

    Article  CAS  PubMed  Google Scholar 

  10. F. Santini, A. Pinchera, A. Marsili, G. Ceccarini, M.G. Castagna, R. Valeriano, M. Giannetti, D. Taddei, R. Centoni, G. Scartabelli, T. Rago, C. Mammoli, R. Elisei, P. Vitti, Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. J. Clin. Endocrinol. Metab. 90, 124–127 (2005)

    Article  CAS  PubMed  Google Scholar 

  11. J. Jonklaas, Sex and age differences in levothyroxine dosage requirement. Endocr. Pract. 16, 71–79 (2010)

    Article  PubMed  Google Scholar 

  12. R.L. Rosenbaum, U.S. Barzel, Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann. Intern. Med. 96, 53–55 (1982)

    Article  CAS  PubMed  Google Scholar 

  13. C.T. Sawin, T. Herman, M.E. Molitch, M.H. London, S.M. Kramer, Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am. J. Med. 75, 206–209 (1983)

    Article  CAS  PubMed  Google Scholar 

  14. M. Devdhar, R. Drooger, M. Pehlivanova, G. Singh, J. Jonklaas, Levothyroxine replacement doses are affected by gender and weight, but not age. Thyroid. 21, 821–827 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. J.A. Loh, L. Wartofsky, J. Jonklaas, K.D. Burman, The magnitude of increased levothyroxine requirements in hypothyroid pregnant women depends upon the etiology of the hypothyroidism. Thyroid. 19, 269–275 (2009)

    Article  CAS  PubMed  Google Scholar 

  16. D.J. Lips, M.T. van Reisen, V. Voigt, W. Venekamp, Diagnosis and treatment of levothyroxine pseudomalabsorption. Neth. J. Med. 62, 114–118 (2004)

    CAS  PubMed  Google Scholar 

  17. M.B. Gordon, M.S. Gordon, Variations in adequate levothyroxine replacement therapy in patients with different causes of hypothyroidism. Endocr. Pract. 5, 233–238 (2004)

    Article  Google Scholar 

  18. L.A. Burmeister, M.O. Goumaz, C.N. Mariash, J.H. Oppenheimer, Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 75, 344–350 (1992)

    CAS  PubMed  Google Scholar 

  19. M. Torlontano, C. Durante, I. Torrente, U. Crocetti, G. Augello, G. Ronga, T. Montesano, L. Travascio, A. Verrienti, R. Bruno, S. Santini, P. D’Arcangelo, B. Dallapiccola, S. Filetti, V. Trischitta, Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients. J. Clin. Endocrinol. Metab. 93, 910–913 (2008)

    Article  CAS  PubMed  Google Scholar 

  20. K.A. Heemstra, H.C. Hoftijzer, W.M. van der Deure, R.P. Peeters, E. Fliers, B.C. Appelhof, W.M. Wiersinga, E.P. Corssmit, T.J. Visser, J.W. Smit, Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis. Clin. Endocrinol. 71, 279–283 (2009)

    Article  CAS  Google Scholar 

  21. E. Lahner, C. Virili, M.G. Santaguida, B. Annibale, M. Centanni, Helicobacter pylori infection and drugs malabsorption. World J. Gastroenterol. 20, 10331–10337 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. M. Centanni, L. Gargano, G. Canettieri, N. Viceconti, A. Franchi, G. Delle Fave, B. Annibale, Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N. Engl. J. Med. 354, 1787–1795 (2006)

    Article  CAS  PubMed  Google Scholar 

  23. S. Checchi, A. Montanaro, L. Pasqui, C. Ciuoli, V. De Palo, M.C. Chiappetta, F. Pacini, L-thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J. Clin. Endocrinol. Metab. 93, 465–469 (2008)

    Article  CAS  PubMed  Google Scholar 

  24. C. Virili, G. Bassotti, M.G. Santaguida, R. Iuorio, S.C. Del Duca, V. Mercuri, A. Picarelli, P. Gargiulo, L. Gargano, M. Centanni, Atypical celiac disease as cause of increased need for thyroxine: a systematic study. J. Clin. Endocrinol. Metab. 97, 419–422 (2012)

    Article  Google Scholar 

  25. M. Cellini, M.G. Santaguida, I. Gatto, C. Virili, S.C. Del Duca, N. Brusca, S. Capriello, L. Gargano, M. Centanni, Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. J. Clin. Endocrinol. Metab. 99, 1454–1458 (2014)

    Article  Google Scholar 

  26. T.G. Bach-Huynh, B. Nayak, J. Loh, S. Soldin, J. Jonklaas, Timing of levothyroxine administration affects serum thyrotropin concentration. J. Clin. Endocrinol. Metab. 94, 3905–3912 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. R. Rajput, S. Chatterjee, M. Rajput, Can levothyroxine be taken as evening dose? Comparative evaluation of morning versus evening dose of levothyroxine in treatment of hypothyroidism. J. Thyroid Res. 505239 (2011). doi:10.4061/2011/505239

    PubMed  PubMed Central  Google Scholar 

  28. C. Cappelli, I. Pirola, E. Gandossi, A. Formenti, M. Castellano, Oral liquid levothyroxine treatment at breakfast: a mistake? Eur. J. Endocrinol. 170, 95–99 (2013)

    Article  PubMed  Google Scholar 

  29. J. Ware Jr, M. Kosinski, S.D. Keller, A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med. Care 34, 220–233 (1996)

    Article  PubMed  Google Scholar 

  30. S.S. Senn, Cross-over Trials in Clinical Research (John Wiley, Chichester, 2002)

    Book  Google Scholar 

  31. M.P. Vanderpump, W.M. Tunbridge, J.M. French, D. Appleton, D. Bates, F. Clark, J. Grimley Evans, D.M. Hasan, H. Rodgers, F. Tunbridge, E.T. Young, The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin. Endocrinol. 43, 55–68 (1995)

    Article  CAS  Google Scholar 

  32. C.T. Sawin, W.P. Castelli, J.M. Hershman, P. McNamara, P. Bacharach, The aging thyroid. Thyroid deficiency in the Framingham Study. Arch. Intern. Med. 145, 1386–1388 (1985)

    Article  CAS  PubMed  Google Scholar 

  33. J.G. Hollowell, N.W. Staehling, W.D. Flanders, W.H. Hannon, E.W. Gunter, C.A. Spencer, L.E. Braverman, Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol. Metab. 87, 489–499 (2002)

    Article  CAS  PubMed  Google Scholar 

  34. G.J. Canaris, N.R. Manowitz, G. Mayor, E.C. Ridgway, The Colorado thyroid disease prevalence study. Arch. Intern. Med. 160, 526–534 (2000)

    Article  CAS  PubMed  Google Scholar 

  35. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I. Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults, Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr. Pract. 18, 988–1028 (2012)

    Article  PubMed  Google Scholar 

  36. M.I. Surks, E. Ortiz, G.H. Daniels, C.T. Sawin, N.F. Col, R.H. Cobin, J.A. Franklyn, J.M. Hershman, K.D. Burman, M.A. Denke, C. Gorman, R.S. Cooper, N.J. Weissman, Subclinical thyroid disease. Scientific review and guidelines for diagnosis and management. JAMA 291, 228–238 (2004)

    Article  CAS  PubMed  Google Scholar 

  37. W. Wiersinga, Thyroid hormone replacement therapy. Horm. Res. 56, 74–81 (2001)

    Article  CAS  PubMed  Google Scholar 

  38. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, Switching levothyroxine from the tablet to the oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-pump inhibitors. J. Clin. Endocrinol. Metab. 99, 4481–4486 (2014)

    Article  CAS  PubMed  Google Scholar 

  39. I. Walter-Sack, C. Clanget, R. Ding, C. Goeggelmann, V. Hinke, M. Lang, J. Pfeilschifter, Y. Tayrouz, K. Weqscheider, Assessment of levothyroxine sodium bioavailability: recommendations for an improved methodology based on the pooled analysis of eight identically designed trials with 396 drug exposures. Clin. Pharmacokinet. 43, 1037–1053 (2004)

    Article  CAS  PubMed  Google Scholar 

  40. M.G. Santaguida, C. Virili, S.C. Del Duca, M. Cellini, I. Gatto, N. Brusca, C. De Vito, L. Gargano, M. Centanni, Thyroxine softgel capsule in patients with gastric-related T4 malabsorption. Endocrine 49, 51–57 (2015)

    Article  CAS  PubMed  Google Scholar 

  41. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. Endocrine 43, 154–160 (2013)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the nurse team (Nadia Biccari, Alberto Pambianco, and Lorena Urbani) of the Endocrine Clinic at the Department of Medicine, University of Perugia, for their excellent assistance. This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Perugia, Perugia, Italy

    Silvia Morelli, Gianpaolo Reboldi, Sonia Moretti, Elisa Menicali & Efisio Puxeddu

  2. Research Centre of Thyroid Proteomics and Genomics (CRiProGeT), University of Perugia, Terni, Italy

    Silvia Morelli, Sonia Moretti, Elisa Menicali, Nicola Avenia & Efisio Puxeddu

  3. Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy

    Nicola Avenia

Authors
  1. Silvia Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gianpaolo Reboldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonia Moretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elisa Menicali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicola Avenia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Efisio Puxeddu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Efisio Puxeddu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morelli, S., Reboldi, G., Moretti, S. et al. Timing of breakfast does not influence therapeutic efficacy of liquid levothyroxine formulation. Endocrine 52, 571–578 (2016). https://doi.org/10.1007/s12020-015-0788-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-015-0788-2

Keywords

Search

Navigation