Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial
Tóm tắt
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 AUC0 − 24 were calculated at the last visit. 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 AUC0 − 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. 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.
Tài liệu tham khảo
Chaker L, Bianco AC, Jonklaas J, Peeters RP, Hypothyroidism. Lancet (London England). 2017;390(10101):1550–62.
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.
Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA. 2008;299(7):769–77.
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.
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.
McAninch EA, Bianco AC. New insights into the variable effectiveness of levothyroxine monotherapy for hypothyroidism. The lancet Diabetes & endocrinology. 2015;3(10):756–8.
Gereben B, McAninch EA, Ribeiro MO, Bianco AC. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat reviews Endocrinol. 2015;11(11):642–52.
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.
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.
Walsh JP. Dissatisfaction with thyroxine therapy - could the patients be right? Curr Opin Pharmacol. 2002;2(6):717–22.
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.
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.
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.
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.
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.
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.
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.
Wiersinga WM. THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect? Eur J Endocrinol. 2017;177(6):R287–r296.
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.
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.
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.
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.
Jonklaas J. Risks and safety of combination therapy for hypothyroidism. Expert Rev Clin Pharmacol. 2016;9(8):1057–67.
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.
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.
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.
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.
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.
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.
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.
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.
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.