Ths paper and abstract is downloadable. It demonstrates that the new T3 derivative has a good display of less vigorous FT3 spikes after taking it. This means that combination users and T3-only users have a better and more stable response. However, this compound will be patented and sold as rather high cost to patients. NDT probably has a similar effect, as most of its T4 and T3 are held in protein molecules, but of course there's no financial pressure to use it. Expect eventually NDT will be superseded.
Clinical ThyroidologyVol. 34, No. 1 HypothyroidismFree Access
Phase 1 Clinical Trial of Poly-Zinc-Liothyronine Demonstrates Slow-Release Serum T3 Kinetics
Elizabeth A. McAninch
Published Online:4 Jan 2022doi.org/10.1089/ct.2022;34....
Review of: Dumitrescu AM, Hanlon EC, Arosemena M, Duchon O, Ettleson MD, Giurcanu M, Bianco AC 2021 Extended absorption of liothyronine from poly-zinc-liothyronine (PZL): Results from a phase 1, double-blind, randomized, and controlled study in humans. Thyroid. Epub 2021 Oct 12. PMID: 34641706.
The standard of care for treatment of hypothyroidism is thyroid hormone replacement with levothyroxine (L-T4) (1). It is becoming more recognized that treatment with L-T4 plus liothyronine (L-T3), termed “combination therapy,” may improve symptoms for some patients who remain dissatisfied with L-T4 alone, despite doses that normalize the serum TSH (1,2). However, the pharmacokinetics of L-T3 have been a significant barrier to this approach, as once-daily L-T3 administration in hypothyroid subjects results supraphysiologic serum peaks and troughs (3); this is a significant excursion from the stable serum T3 levels exhibited in individuals with endogenous euthyroidism (4). Perhaps not surprisingly, in over a dozen clinical trials, combination therapy has not been shown to have definite superiority over L-T4 monotherapy (5,6), but the available L-T3 formulations used in these trials did not mimic physiologic, endogenous T3 supply well. Thus, in a consensus document from the American, European, and British Thyroid Associations, there is agreement among all 34 of 34 experts that new formulations of L-T3 are desirable to use in future clinical trials to assess combination therapy (2). Several groups of investigators are developing exciting new technologies to deliver L-T3 with improved pharmacokinetics. After showing promise in a rodent model (7), the authors of this study performed a Phase 1 clinical trial of a metal coordinated poly-zinc-liothyronine (PZL) (8).
This was a Phase 1 clinical trial of 12 healthy adult volunteers, ages 18 to 50 (4 women and 8 men). Subjects had no history of thyroid disease and no past history of gastrointestinal disorders. All participants had a normal electrocardiogram (ECG) and serum thyroid function tests (TFTs) at baseline.
Subjects were admitted as inpatients in the morning after an overnight fast. They were randomly assigned to treatment sequence arms and were given one dose of placebo, PZL containing 50 µg of T3, or sodium-T3 containing 50 µg of T3 in identical capsules coated for duodenal delivery. The subjects were observed for 48 hours, during which timed blood draws were used to determine pharmacokinetics, three examinations were performed each day, and ECG was performed prior to discharge. After 2-week washout periods, the sequence was repeated so that all participants received each treatment. An independent physician who was not blinded to treatment acted as the safety monitor. One participant was excluded after not completing all study arms; 11 participants completed all 3 arms of the trial.
In the L-T3 arm, serum T3 levels rose from a baseline of approximately 110 ng/dl to a peak concentration (Cmax) of approximately 300 ng/dl between 2 and 3 hours after the dose (Figure 1A). After approximately 8 hours, serum T3 levels had decreased to half of Cmax. Serum T3 levels returned to baseline between 36 and 46 hours.
Figure 1. Intestinal absorption of sodium T3 capsules versus poly-zinc-liothyronine (PZL).
(A) When T3 was administered once daily in healthy, euthyroid participants, serum T3 levels rose to a transient supratherapeutic peak, about 2 to 3 hours after ingestion. After approximately 8 hours, serum T3 levels had decreased to half of the peak concentrations, and they returned to baseline between hours 36 and 46. (B) When PZL was administered once daily, serum T3 levels rose to a relatively lesser peak between hours 2 and 8. Serum T3 concentrations still exceeded half of the peak concentration by 24 hours and returned to baseline by 46 hours.
Created by Elizabeth A. McAninch MD.
In the PZL arm, serum T3 levels rose from baseline of approximately 110 ng/dl to a Cmax of approximately 220 ng/dl between 2 and 8 hours after the dose (Figure 1B). By 24 hours, serum T3 concentration still exceeded half of Cmax. Serum T3 levels returned to baseline by 46 hours.
In the placebo arm, serum T3 levels were relatively stable, ranging from approximately 100-115ng/dL. Serum TSH was similarly reduced in the L-T3 and PZL arms and decreased by approximately 40% at 9 hours and by approximately 70% by 24 hours, disrupting the circadian rhythmicity observed with the placebo.
No differences in heart rate, blood pressure, or sleep outcomes were seen between the three arms. There were no serious adverse events in any treatment arm. Mild adverse events were evenly distributed among arms and resolved without complications; none were definitely linked to L-T3 or PZL use.
In this Phase 1 clinical trial, euthyroid adults treated with PZL demonstrated a slower-release serum T3 profile illustrated by a lower T3 serum peak compared with participants treated with L-T3, and maintenance of serum T3 concentrations above those for placebo for a longer duration. These findings are consistent with delayed but continued intestinal absorption of PZL use, compared with L-T3.
In this small placebo-controlled study of PZL versus L-T3, there were no adverse reactions and adverse events were similar in all treatment arms. This is consistent with other recent studies that have not demonstrated harm with L-T3 use at doses that maintain a normal serum TSH (6,9,10). This will, of course, continue to be the source of further interest if PZL moves to the next phases of clinical trials, and I interpret these findings with cautious optimism.
That the NIH funded this study may provide further evidence, and hope for our patients, that there is better acknowledgment of residual symptomatology in a minority of persons with hypothyroidism and that none of the currently available treatment methods provide absolutely physiologic thyroid replacement. Hypothyroidism has high prevalence, and thus is a public health topic of great value deserving of improved solutions, in my opinion. PZL represents one new technological attempt to improve T3 pharmacokinetics (7,8).
My clinical practice is perhaps biased due to my documented research and clinical interest in the field because in the contemporary (internet) era, patients can easily access research, medical journalism, and peer support groups. Thus, it is not uncommon for me to encounter a hypothyroid patient with residual symptoms that may be attributed to hypothyroidism, despite treatment with L-T4 monotherapy that normalizes the serum TSH concentration. In the absence of contraindications, I often offer n-of-1 therapeutic trials with L-T4+L-T3 combination therapy, during which patients may either: (a) report a positive response, (b) report no symptomatic differences, or (c) feel worse, which typically is associated with palpitations, anxiety or bothersome bursts of energy followed by fatigue, depending on the timing of the L-T3 doses. I have not found a strong clinical predictor of which patient will have which response. The multiple-times-per-day dosing regimen is a downside to L-T3, as well as not being able to provide a definite outline of the risks of intermittent supratherapeutic serum T3 levels. It is unknown whether clinical trials, or n-of-1 therapeutic trials in our practices, performed with a slow-release formulation, such as PZL in the current study (8), will show superiority to L-T4 alone.