Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial.
Clinical trial
Combination therapy levothyroxine
Hypothyroidism
Liothyronine
Journal
BMC endocrine disorders
ISSN: 1472-6823
Titre abrégé: BMC Endocr Disord
Pays: England
ID NLM: 101088676
Informations de publication
Date de publication:
28 Aug 2023
28 Aug 2023
Historique:
received:
26
12
2022
accepted:
16
08
2023
medline:
31
8
2023
pubmed:
29
8
2023
entrez:
28
8
2023
Statut:
epublish
Résumé
Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13 . Registration date: 08/12/2021.
Sections du résumé
BACKGROUND
BACKGROUND
Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients.
METHODS
METHODS
Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC
RESULTS
RESULTS
Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC
CONCLUSION
CONCLUSIONS
Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested.
IRCT REGISTRATION NUMBER
UNASSIGNED
IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13 . Registration date: 08/12/2021.
Identifiants
pubmed: 37641049
doi: 10.1186/s12902-023-01434-y
pii: 10.1186/s12902-023-01434-y
pmc: PMC10463362
doi:
Substances chimiques
Triiodothyronine
06LU7C9H1V
Thyroxine
Q51BO43MG4
Delayed-Action Preparations
0
Iodine Radioisotopes
0
Types de publication
Randomized Controlled Trial
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
182Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Chaker L, Bianco AC, Jonklaas J, Peeters RP, Hypothyroidism. Lancet (London England). 2017;390(10101):1550–62.
doi: 10.1016/S0140-6736(17)30703-1
pubmed: 28336049
Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med. 1987;316(13):764–70.
doi: 10.1056/NEJM198703263161302
pubmed: 3821822
Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008;299(7):769–77.
doi: 10.1001/jama.299.7.769
pubmed: 18285588
Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE. 2011;6(8):e22552.
doi: 10.1371/journal.pone.0022552
pubmed: 21829633
pmcid: 3148220
Peterson SJ, McAninch EA, Bianco AC. Is a normal TSH synonymous with “Euthyroidism” in Levothyroxine Monotherapy? J Clin Endocrinol Metab. 2016;101(12):4964–73.
doi: 10.1210/jc.2016-2660
pubmed: 27700539
pmcid: 6287526
McAninch EA, Bianco AC. New insights into the variable effectiveness of levothyroxine monotherapy for hypothyroidism. The lancet Diabetes & endocrinology. 2015;3(10):756–8.
doi: 10.1016/S2213-8587(15)00325-3
Gereben B, McAninch EA, Ribeiro MO, Bianco AC. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat reviews Endocrinol. 2015;11(11):642–52.
doi: 10.1038/nrendo.2015.155
Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. 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):577–85.
doi: 10.1046/j.1365-2265.2002.01654.x
Wekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JG, Wiersinga WM. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol. 2005;153(6):747–53.
doi: 10.1530/eje.1.02025
pubmed: 16322379
Walsh JP. Dissatisfaction with thyroxine therapy - could the patients be right? Curr Opin Pharmacol. 2002;2(6):717–22.
doi: 10.1016/S1471-4892(02)00209-6
pubmed: 12482736
Werneck de Castro JP, Fonseca TL, Ueta CB, McAninch EA, Abdalla S, Wittmann G, Lechan RM, Gereben B, Bianco AC. Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Investig. 2015;125(2):769–81.
doi: 10.1172/JCI77588
pubmed: 25555216
pmcid: 4319436
Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592–9.
doi: 10.1210/jc.2006-0448
pubmed: 16670166
Wiersinga WM. T4 + T3 combination therapy: an Unsolved Problem of increasing magnitude and complexity. Front Endocrinol. 2021;36(5):938–51.
Jonklaas J, Burman KD, Wang H, Latham KR. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther Drug Monit. 2015;37(1):110–8.
doi: 10.1097/FTD.0000000000000113
pubmed: 24977379
pmcid: 5167556
Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM. Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Exp Clin Endocrinol Diabetes. 2007;115(4):261–7.
doi: 10.1055/s-2007-973071
pubmed: 17479444
Van Tassell B, Wohlford GFt, Linderman JD, Smith S, Yavuz S, Pucino F, Celi FS. Pharmacokinetics of L-Triiodothyronine in patients undergoing thyroid hormone therapy withdrawal. Thyroid: official journal of the American Thyroid Association. 2019;29(10):1371–9.
doi: 10.1089/thy.2019.0101
pubmed: 31364488
Surks MI, Schadlow AR, Oppenheimer JH. A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement. J Clin Investig. 1972;51(12):3104–13.
doi: 10.1172/JCI107137
pubmed: 4539287
pmcid: 332992
Azizi F, Amouzegar A, Mehran L, Abdi H. LT4 and slow release T3 combination: Optimum Therapy for Hypothyroidism? Int J Endocrinol Metab. 2020;18(2):e100870.
doi: 10.5812/ijem.100870
pubmed: 32636887
pmcid: 7322563
Wiersinga WM. THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect? Eur J Endocrinol. 2017;177(6):R287–r296.
doi: 10.1530/EJE-17-0645
pubmed: 28855267
Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, McAninch EA, Moeller LC, Nygaard B, Sawka AM, et al. Evidence-based use of Levothyroxine/Liothyronine combinations in treating hypothyroidism: a Consensus Document. Thyroid. 2021;31(2):156–82.
doi: 10.1089/thy.2020.0720
pubmed: 33276704
pmcid: 8035928
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA Guidelines: the Use of L-T4 + L-T3 in the treatment of Hypothyroidism. Eur thyroid J. 2012;1(2):55–71.
doi: 10.1159/000339444
pubmed: 24782999
pmcid: 3821467
Hennemann G, Docter R, Visser T, Postema P, Krenning E. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid. 2004;14(4):271–5.
doi: 10.1089/105072504323030924
pubmed: 15142360
Amouzegar A, Delshad H, Mehran L, Tohidi M, Khafaji F, Azizi F. Reference limit of thyrotropin (TSH) and free thyroxine (FT4) in thyroperoxidase positive and negative subjects: a population based study. J Endocrinol Investig. 2013;36(11):950–4.
Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid: official journal of the American Thyroid Association. 2004;14(4):271–5.
doi: 10.1089/105072504323030924
pubmed: 15142360
Jonklaas J. Risks and safety of combination therapy for hypothyroidism. Expert Rev Clin Pharmacol. 2016;9(8):1057–67.
doi: 10.1080/17512433.2016.1182019
pubmed: 27137849
Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, van Weert HC, Wiersinga WM. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666–74.
doi: 10.1210/jc.2004-2111
pubmed: 15705921
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340(6):424–9.
doi: 10.1056/NEJM199902113400603
pubmed: 9971866
Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. 2003;290(22):2952–8.
doi: 10.1001/jama.290.22.2952
pubmed: 14665656
Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895–902.
doi: 10.1530/EJE-09-0542
pubmed: 19666698
Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr practice: official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2005;11(4):223–33.
doi: 10.4158/EP.11.4.223
Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3’-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551–5.
doi: 10.1210/jc.2003-030139
pubmed: 14557420
Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, Momtazi S, Musavinasab N, Hayatbakhsh MR. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80–9.
doi: 10.1080/07435800903156340
pubmed: 19701833
Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98(5):1982–90.
doi: 10.1210/jc.2012-4107
pubmed: 23539727
Santini F, Giannetti M, Ricco I, Querci G, Saponati G, Bokor D, Rivolta G, Bussi S, Braverman LE, Vitti P, et al. Steady-state serum T3 concentrations for 48 hours following the oral administration of a single dose of 3,5,3’-Triiodothyronine sulfate (T3S). Endocr practice: official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2014;20(7):680–9.
doi: 10.4158/EP13331.OR