ESPE Yearbook of Paediatric Endocrinology

Thyroid. 2022 Feb;32(2):196-205. doi: 10.1089/thy.2021.0304. Epub 2021 Dec 31. PMID: 34641706

Brief Summary: This phase 1, double-blind, randomized, single-dose, placebo-controlled, crossover study compared pharmacokinetics, pharmacodynamics, incidence of adverse events, and sleep pattern between the routinely used L-triiodothyronine (LT3) and a newly developed metal-coordinated form of LT3 (poly-zinc-liothyronine, PZL) in 12 healthy volunteers (4 women, 8 men, aged 18-50 years with normal thyroid function). PZL showed more stable pharmacokinetics compared to LT3.

Combination therapy of levothyroxine (LT4) together with LT3, or LT3 alone, may improve symptoms of hypothyroidism and quality of life in adult patients [1,2,3]. However, LT3 administration results in a supraphysiological peak in the first 6 hours after intake associated sometimes with adverse effects, limiting its routine use. A recent consensus statement of the international Thyroid Associations (ATA, ETA, BTA) proposed further research on LT4+LT3 combination drugs [1].

PZL is a newly developed LT3 prodrug with sustained-release due to a supramolecular metal-coordinated complex. The poly-zinc metal complex of the prodrug extends the intestinal transit time and allows slow release of LT3. This study provides convincing pharmacokinetic-pharmacodynamic data on PZL. The concentration peak after intake of PZL is 30% lower, but maintains T3 levels at a higher level after 12 hours of intake. The T3 serum profile of PZL was not associated with differences in heart rate, blood pressure, or sleep, nor further adverse events compared to LT3 or placebo.

In summary, this small phase 1 study provides very promising results on the pharmacokinetic-pharmacodynamic properties of PZL. Such a new drug has the potential to improve wellbeing of hypothyroid patients. As LT3 treatment has also been used in congenital hypothyroidism, PZL might be of interest for pediatric endocrinologists as well [4]. Larger randomized controlled studies in patients with hypothyroidism are eagerly awaited.

References: 1. Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, McAninch EA, Moeller LC, Nygaard B, Sawka AM, Watt T, Dayan CM. Thyroid. 2021 Feb;31(2):156-182. doi: 10.1089/thy.2020.0720. 2. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, van Weert HC, Wiersinga WM. J Clin Endocrinol Metab. 2005 May;90(5):2666-74. doi: 10.1210/jc.2004-2111. Epub 2005 Feb 10. PMID: 15705921. 3. Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study. Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Omdal LJ, Lee-Ødegård S, Eriksen EF. Front Endocrinol (Lausanne). 2022 Feb 22;13:816566. doi: 10.3389/fendo.2022.816566. eCollection 2022. PMID: 35273566. 4. Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone. Paone L, Fleisch AF, Feldman HA, Brown RS, Wassner AJ. J Pediatr. 2016 Aug;175:167-172.e1. doi: 10.1016/j.jpeds.2016.04.022. Epub 2016 May 11. PMID: 27178621.