ESPE Abstracts

Background and Objectives: MCT8 deficiency is a debilitating, ultra-rare, X-linked disorder resulting from dysfunctional thyroid hormone (TH) transport. A lack of TH in the brain results in profound neurodevelopmental delay while a co-existing excess of TH in tissues outside the brain leads to symptoms of chronic thyrotoxicosis. Tiratricol is a naturally occurring metabolite of triiodothyronine (T3) that clinical trials have shown can restore normal TH signalling. This study investigates the pharmacokinetics (PK) of tiratricol.

Methods: This novel Phase 1, randomized, five-period cross-over study was a hybrid combination of a two-period cross-over and a three-period balanced incomplete block design in healthy adult male subjects (n = 30) with a washout of ≥3 days between periods. Single oral doses of tiratricol were administered (see table). The primary objective was to establish bioequivalence between 350μg tiratricol oblong tablets and 350μg tiratricol round tablets. The secondary objectives were to estimate the effect of food by comparing both 175μg and 1050μg tiratricol oblong tablet doses in fasted versus fed states, and to assess dose-proportionality of tiratricol oblong tablets in a fasted state. All subjects received the treatments for the critical assessment of bioequivalence and 3 additional ones. Serum tiratricol, standard PK parameters, and safety were assessed.

Results: Bioequivalence was established between 350μg tiratricol oblong and 350μg tiratricol round tablets in terms of AUC and Cmax with a serum half-life of approximately 13h for both administrations. Overall exposure (AUC) was comparable between the fasted and fed state. Absorption was rapid in the fasted state (median Tmax 0.5 hr) but slower in the fed state (median Tmax approximately 1.5 hr), with Cmax 67–70% lower. Cmax following treatment with the 175μg, 350μg, and 1050μg oblong tablet doses increased proportionally with increasing dose, whereas AUC increased in a slightly greater than proportional manner with increasing dose. Tiratricol was well tolerated in all doses and fasting states, with no serious adverse events recorded.

Conclusions: In this novel study, robust PK data for tiratricol was generated for the first time, establishing bioequivalence between the round tablet and the oblong tablet, and characterizing the effects of food and the PK properties of increased dosing.