Extended absorption of liothyronine from poly-zinc-liothyronine: results from a phase 1, double-blind, randomized, and controlled study in humans
Open accessAbstract
Background: L-triiodothyronine (LT3) has been increasingly used in combination with levothyroxine in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical triiodothyronine (T3) peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics (PK) of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) incidence of adverse events, and (iv) exploratory analysis of the sleep patterns after LT3, PZL, or placebo (PB) administration. Methods: Twelve healthy volunteers 18–50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose PB-controlled, crossover study to compare PZL against LT3 or PB. Subjects were admitted three separate times to receive a randomly assigned capsule containing PB, 50 μg LT3, or 50 μg PZL, and were observed for 48 hours. A 2-week washout period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a T max at 2 hours and return to basal levels by 24–36 hours. PZL-derived serum T3 levels exhibited ∼30% lower C max that was 1 hour delayed and extended into a plateau that lasted up to 6 hours. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded ½ of C max . Thyrotropin levels were similarly reduced in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 PK. PZL is on track to provide hypothyroid patients with stable levels of serum T3.
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In healthy volunteers, after poly-zinc-LT3 administration, serum T3 levels at 24 h still exceeded half of Cmax.
“This was followed by a lower but much longer plateau; by 24 h, serum T3 levels still exceeded half of Cmax.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
In healthy volunteers, TSH levels were similarly reduced in poly-zinc-LT3 and LT3 groups.
“TSH levels were similarly reduced in both groups (64).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
In healthy volunteers, poly-zinc-LT3-derived serum T3 exhibited an approximately 30% lower Cmax that was delayed by 1 h and extended into a plateau lasting up to 6 h, compared with LT3-derived T3.
“While LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at ~2 h and return to basal levels by 24–36 h, poly-zinc-LT3-derived serum T3 levels exhibited an approximately 30% lower Cmax that was delayed by 1 h and extended into a plateau that lasted up to 6 h.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
Poly-zinc-LT3 possesses the necessary properties to achieve improved T3 pharmacokinetics with stable serum T3 levels.
“These data indicate that poly-zinc-LT3 possesses the necessary properties to achieve an improved T3 PK, with stable levels of serum T3.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
In healthy volunteers, the areas under the curve for poly-zinc-LT3 and LT3 were similar.
“Remarkably the areas under the curves were similar, indicating that similar amounts of T3 were absorbed but with substantially different PK.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
The similar AUCs indicate that similar amounts of T3 were absorbed from poly-zinc-LT3 and LT3 but with substantially different pharmacokinetics.
“Remarkably the areas under the curves were similar, indicating that similar amounts of T3 were absorbed but with substantially different PK.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [64]
In a phase I, double-blind RCT of 12 healthy volunteers, PZL showed a 1 hour later Tmax, an approximately 30% lower Cmax, and an approximately 6-hour T1/2, with hemodynamic and sleep parameters not significantly different between PZL and conventional T3 groups.
“The researchers subsequently conducted a phase I, double-blind RCT of 12 healthy volunteers (180). Laboratory tests showed a release profile similar to the previous animal study: a 1 hour later Tmax, an ∼30% lower Cmax, and an ∼6-hour T1/2. The hemodynamic and sleep parameters were not significantly different between the PZL and conventional T3 groups.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [180]
A large proportion of articles on LT4 nanomaterials only extended the studies to in vitro experiments and few proceeded to animal or human studies.
“However, a large proportion of articles only extended the studies to in vitro experiments and few of them proceeded to animal or human studies (179, 180, 272).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [180]
The pharmacokinetic properties and biocompatibility of LT4 nanomaterials remained untested.
“The pharmacokinetic properties and biocompatibility remained untested.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [180]
A phase 1 trial comparing PZL and LT3 showed a 6-hour plateau in serum T3 Cmax for PZL, which was 30% lower than that for LT3.
“A phase 1 trial comparing PZL and LT3 showed a 6-hour plateau in serum T3 Cmax for PZL, which was 30% lower than that for LT3.”
T3 remained at over half of the Cmax for more than 24 h with PZL.
“Furthermore, T3 remained at over half of the Cmax for more than 24 h (52).”
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- Authors
- Dumitrescu, A. M., Hanlon, E. C., Arosemena, M., Duchon, O., Ettleson, M., Giurcanu, M., & Bianco, A. C.
- Affiliations
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Chicago, Illinois, USA.
- University of Chicago (US)
- University of Chicago Medical Center (US)
- Corresponding author
- Dumitrescu, Alexandra M.
- Bianco, Antonio C.
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2022-02
- Volume
- 32
- Issue
- 2
- Pages
- 196-205
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC8861912
- OpenAlex
- W3207590171
- Cited by
- 20
- References
- 44
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 1
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Thyroid (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R44DK116396, P30DK020595, T32DK007011)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- liothyronine, triiodothyronine, pharmacokinetics, pharmacodynamics, hypothyroidism, thyroid-stimulating hormone, sleep patterns, adverse events, healthy volunteers
- MeSH terms
- Adolescent, Adult, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Hypothyroidism, Male, Middle Aged, Triiodothyronine, Zinc, Hormone Replacement Therapy, Young Adult
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