Evicenter
P&T meetings

Emcitate (tiratricol)

MCT8 deficiency

Last updated
78 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Pharmacodynamics

7 evidence topics · 6 sources

Concentration-dependent T3 lowering

“Tiratricol reduces elevated T3 concentrations in patients with MCT8 deficiency in a concentration-dependent manner, with greater T3-lowering effect at higher tiratricol exposures; however, this effect plateaus at or above mean tiratricol concentrations of approximately 746 ng/dL in patients 5 years and older.” (opens the prescribing information at this quote)

“Following discontinuation of EMCITATE, total T3 concentrations increased toward pretreatment levels within one week.” (opens the prescribing information at this quote)

Exposure-response relationship and TSH suppression

“This suggests that dosing tiratricol higher than a mean concentration of 15 nmol/L (corresponding to an AUC of 360 nmol*24h/L and a daily dose of ~ 80 µg / kg) has a limited additional effect on serum T3.” (opens the source at this quote in a new tab)

“The study of Everts and colleagues (Everts et al., 1994) shows that Triac uptake into anterior pituitary cells isolated from adult WT rats is higher compared to uptake of T3. Moreover, Triac was shown to be more potent to suppress TSH secretion compared to T3.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“There is insufficient information to characterize the effect of tiratricol on the QTc interval.” (opens the prescribing information at this quote)

“Tiratricol produced a concentration-dependent inhibition of hERG tail current amplitude by 5.0 ± 1.4%, 12.2 ± 2.1%, 16.8 ± 1.3% and 23.0 ± 2.0% in the presence of TIRATRICOL at 0.1, 1, 10 and 30 µmol/L, respectively. This inhibition was statistically significant (p<0.01).” (opens the source at this quote in a new tab)

Human cerebral organoid study

“Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients.” (opens the source at this quote in a new tab)

“We next treated for 24 hours control and MCT8-deficient COs with 10 nM T3 and equivalent doses of DITPA (3.5 μM) or TRIAC (10 nM) and measured T3-responsive genes.” (opens the source at this quote in a new tab)

“Overall, these results indicate that the T3 signaling in the MCT8-deficient COs might be compromised and represent a proof of concept that the thyromimetic molecules TRIAC and DITPA can act in human neural cells despite a nonfunctional MCT8.” (opens the source at this quote in a new tab)

“In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3′,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS.” (opens the source at this quote in a new tab)

Preclinical findings in Mct8/Oatp1c1 double knockout mice

“Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency.” (opens the source at this quote in a new tab)

“Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks.” (opens the source at this quote in a new tab)

“Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks.” (opens the source at this quote in a new tab)

“Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.” (opens the source at this quote in a new tab)

Preclinical findings concerning T4 suppression

“The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO).” (opens the source at this quote in a new tab)

“Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g of body weight/day, given in drinking water, from postnatal day 21 to 30.” (opens the source at this quote in a new tab)

“TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO mice.” (opens the source at this quote in a new tab)

“Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels.” (opens the source at this quote in a new tab)

“The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.” (opens the source at this quote in a new tab)

Commentary on the preclinical T4 findings

“The study by Bárez-López et al. is important as it shows that Triac can attenuate the thyrotoxicosis of Mct8 KO mice.” (opens the source at this quote in a new tab)

“However, the results based on studies performed on Mct8 KO mouse brains should be interpreted in the context of the model used and the safety profile obtained in humans.” (opens the source at this quote in a new tab)

“First, as Mct8 KO mice lack any overt neurological deficit, they do not provide an optimal model for the neurocognitive phenotype of AHDS.” (opens the source at this quote in a new tab)

“As in other clinical settings (TH resistance, thyroid cancer), the beneficial peripheral effects of Triac are mediated by potent suppression of TSH secretion with consequent decreases in serum TH levels.” (opens the source at this quote in a new tab)