Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations

References

• Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: Management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–228.
   PubMedGoogle Scholar
• Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751.
   PubMed Web of Science ®Google Scholar
• Kahaly GJ. Therapeutic use of levothyroxine: a historical perspective. In: Kahaly GJ, editor, 70 Years of levothyroxine. Switzerland: Springer Nature Switzerland AG; 2021. pp 1–11.
   Google Scholar
• Utiger RD. Thyrotrophin radioimmunoassay: another test of thyroid function. Ann Intern Med. 1971;74(4):627–629.
   PubMed Web of Science ®Google Scholar
• Braverman LE, Ingbar SH, Sterling K. Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin Invest. 1970;49(5):855–864.
   PubMed Web of Science ®Google Scholar
• Razvi SR. Levothyroxine in the older patient. In: Kahaly GJ, editor, 70 Years of levothyroxine. Switzerland: Springer Nature Switzerland AG; 2021. pp 75–84.
   Google Scholar
• Razvi S, Hostalek U. Therapeutic challenges in the application of serum thyroid stimulating hormone testing in the management of patients with hypothyroidism on replacement thyroid hormone therapy: a review. Curr Med Res Opin. 2019;35(7):1215–1220.
   PubMed Web of Science ®Google Scholar
• Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ. 2019;366:l4892.
   PubMed Web of Science ®Google Scholar
• Eligar V, Taylor PN, Okosieme OE, et al. Thyroxine replacement: a clinical endocrinologist's viewpoint. Ann Clin Biochem. 2016;53(Pt 4):421–433.
   PubMed Web of Science ®Google Scholar
• Habet S. Narrow therapeutic index drugs: clinical pharmacology perspective. J Pharm Pharmacol. 2021;73(10):1285–1291.
   PubMed Web of Science ®Google Scholar
• Committee For Medicinal Products For Human Use (CHMP). Draft guideline on the investigation of bioequivalence; [cited 2022 Mar]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-investigation-bioequivalence_en.pdf.
   Google Scholar
• European Medicines Agency. Committee for Proprietary medicinal Products (CPMP). Note for guidance on the investigation of bioavailability and bioequivalence. 2009; [cited 2022 Mar]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003519.pdf.
   Google Scholar
• US Department of Health and Human Services. Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry: levothyroxine sodium tablets – in vivo pharmacokinetic and bioavailability studies and in vitro dissolution testing; CDER; 2000; [cited 2022 Mar]. Available from: www.fda.gov/cder/guidance/index.htm.
   Google Scholar
• Lipp HP, Hostalek U. A new formulation of levothyroxine engineered to meet new specification standards. Curr Med Res Opin. 2019;35(1):147–150.
   PubMed Web of Science ®Google Scholar
• Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87(7):3221–3226.
   PubMed Web of Science ®Google Scholar
• Duntas LH, Jonklaas J. Levothyroxine dose adjustment to optimise therapy throughout a patient's lifetime. Adv Ther. 2019;36(Suppl 2):30–46.
   PubMed Web of Science ®Google Scholar
• Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365:l2006.
   PubMed Web of Science ®Google Scholar
• Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA. 2018;320(13):1349–1359.
   PubMed Web of Science ®Google Scholar
• Trimboli P, Scappaticcio L, De Bellis A, et al. Different formulations of levothyroxine for treating hypothyroidism: a real-life study. Int J Endocrinol. 2020;2020:4524759. 2020:4524759.
   PubMed Web of Science ®Google Scholar
• Richou M, Gilly O, Taillard V, et al. Levothyroxine dose adjustment in hypothyroid patients following gastric sleeve surgery. Ann Endocrinol. 2020;81(5):500–506.
   PubMed Web of Science ®Google Scholar
• Fierabracci P, Martinelli S, Tamberi A, et al. Weight loss and variation of levothyroxine requirements in hypothyroid obese patients after bariatric surgery. Thyroid. 2016;26(4):499–503.
   PubMed Web of Science ®Google Scholar
• British National Formulary. Levothyroxine sodium; [cited 2022 Mar]. Available from: https://bnf.nice.org.uk/medicinal-forms/levothyroxine-sodium.html.
   Google Scholar
• Heads of Medicines Agencies; [cited 2022 Mar]. Available from: https://www.hma.eu.
   Google Scholar
• ClinCalc.com. Levothyroxine. Drug Usage Statistics, United States, 2013–2019; [cited 2022 Mar]. Available from: https://clincalc.com/DrugStats/Drugs/Levothyroxine.
   Google Scholar
• Elnaem MH, Irwan NA, Abubakar U, et al. Impact of medication regimen simplification on medication adherence and clinical outcomes in patients with long-term medical conditions. Patient Prefer Adherence. 2020;14:2135–2145.
   PubMed Web of Science ®Google Scholar
• Ingersoll KS, Cohen J. The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med. 2008;31(3):213–224.
   PubMed Web of Science ®Google Scholar
• Ayele AA, Tegegn HG, Ayele TA, et al. Medication regimen complexity and its impact on medication adherence and glycemic control among patients with type 2 diabetes mellitus in an ethiopian general hospital. BMJ Open Diabetes Res Care. 2019;7(1):e000685.
   PubMed Web of Science ®Google Scholar
• Kumar R, Shaukat F. Adherence to levothyroxine tablet in patients with hypothyroidism. Cureus. 2019;11:e4624.
   PubMed Web of Science ®Google Scholar
• Crilly M. Thyroxine adherence in primary hypothyroidism (letter). Lancet. 2004;363(9420):1558.
   PubMed Web of Science ®Google Scholar
• El Helou S, Hallit S, Awada S, et al. Adherence to levothyroxine among patients with hypothyroidism in Lebanon. East Mediterr Health J. 2019;25(3):149–159.
   PubMed Web of Science ®Google Scholar
• Machado-Alba JE, Machado-Duque ME. Adherence to levothyroxine prescription in patients with hypothyroidism. Rev Med Chil. 2020;148(6):740–745.
   PubMed Web of Science ®Google Scholar
• Topaloğlu Ö, Yavuz A, Tiryaki Aylıkcı AB. Evaluation of adherence to levothyroxine and out-of-range thyroid-stimulating hormone levels in pregnant women with primary hypothyroidism. Int J Clin Pract. 2021;75(8):e14312.
   PubMed Web of Science ®Google Scholar
• Cappelli C, Castello R, Marini F, et al. Adherence to levothyroxine treatment among patients with hypothyroidism: a northeastern Italian survey. Front Endocrinol. 2018;9:699.
   PubMed Web of Science ®Google Scholar
• Hepp Z, Lage MJ, Espaillat R, et al. The association between adherence to levothyroxine and economic and clinical outcomes in patients with hypothyroidism in the US. J Med Econ. 2018;21(9):912–919.
   PubMed Web of Science ®Google Scholar
• Davoren P. Modern management of thyroid replacement therapy. Aust Prescr. 2008;31(6):159–161.
   Web of Science ®Google Scholar
• Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British thyroid association executive committee. Clin Endocrinol. 2016;84(6):799–808.
   PubMed Web of Science ®Google Scholar
• Flinterman LE, Kuiper JG, Korevaar JC, et al. Impact of a forced dose-equivalent levothyroxine Brand switch on plasma thyrotropin: a cohort study. Thyroid. 2020;30(6):821–828.
   PubMed Web of Science ®Google Scholar
• New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE). Some medicines need to be prescribed by brand; [cited 2022 Mar]. Available from: https://www.medsafe.govt.nz/profs/PUArticles/December2019/Some-medicines-need-to-be-prescribed-by-brand.htm.
   Google Scholar
• Benvenga S, Carlé A. Levothyroxine formulations: pharmacological and clinical implications of generic substitution. Adv Ther. 2019;36(Suppl 2):59–71.
   PubMed Web of Science ®Google Scholar
• Fliers E, Demeneix B, Bhaseen A, et al. European thyroid association (ETA) and thyroid federation international (TFI) joint position statement on the interchangeability of levothyroxine products in EU countries. Eur Thyroid J. 2018;7(5):238–242.
   PubMed Web of Science ®Google Scholar
• Katz M, Scherger J, Conard S, et al. Healthcare costs associated with switching from Brand to generic levothyroxine. Am Health Drug Benefits. 2010;3(2):127–134.
   PubMedGoogle Scholar
• Brito JP, Ross JS, Sangaralingham L, et al. Comparative effectiveness of generic vs Brand-Name levothyroxine in achieving normal thyrotropin levels. JAMA Netw Open. 2020;3(9):e2017645.
   PubMed Web of Science ®Google Scholar
• Gottwald-Hostalek U, Uhl W, Wolna P, et al. New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin. 2017;33(2):169–174.
   PubMed Web of Science ®Google Scholar
• Jonklaas J. Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level. Curr Opin Endocrinol Diabetes Obes. 2017;24:356–363.
   PubMedGoogle Scholar
• Saravanan P, Chau WF, Roberts N, et al. Psychological well-being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based questionnaire study. Clin Endocrinol. 2002;57(5):577–585.
   PubMed Web of Science ®Google Scholar
• Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ. 2001;323(7318):891–895.
   PubMed Web of Science ®Google Scholar
• Hoermann R, Midgley JE, Larisch R, et al. Homeostatic control of the Thyroid-Pituitary axis: Perspectives for diagnosis and treatment. Front Endocrinol. 2015;6(177):177.
   PubMed Web of Science ®Google Scholar
• Li E, Yen PM, Dietrich JW, et al. Profiling retrospective thyroid function data in complete thyroidectomy patients to investigate the HPT axis set point (PREDICT-IT). J Endocrinol Invest. 2021;44(5):969–977.
   PubMed Web of Science ®Google Scholar
• Bianco AC, Kim BS. Pathophysiological relevance of deiodinase polymorphism. Curr Opin Endocrinol Diabetes Obes. 2018;25(5):341–346.
   PubMedGoogle Scholar