Abstract Details

Title The Pharmacokinetics and Safety of Deuterated-Tetrabenazine

Topic Movement Disorders

Presentation(s) P07 - (-)

Poster/Presentation
Number 210

Objective

Background BACKGROUND: TBZ is approved for the treatment of chorea associated with HD. TBZ is rapidly and extensively converted to active metabolites ?-dihydrotetrabenazine (HTBZ) and ?-HTBZ, which are in turn metabolized by CYP2D6-mediated O-demethylation. Limitations of TBZ include frequent dosing, short half-life (of metabolites) and high peak concentrations which are often associated with important side effects. SD-809 is a deuterated form of TBZ in which selective deuterium (D)-substitution for hydrogen attenuates the metabolism of ?-HTBZ and ?-HTBZ without altering their pharmacological properties.

Design/Methods DESIGN/METHODS: A randomized, double-blind, two-period, crossover study in healthy volunteers receiving single oral 25 mg doses of SD-809 or TBZ (powder in capsule). The alternate treatment was given after 72 hours of PK sampling and washout.

Results RESULTS: 21 subjects were dosed and 19 had evaluable PK. SD-809 and TBZ plasma concentrations were unmeasurable in most samples and, when assessable, did not differ. Concentrations of deuterated (?+?)-HTBZ (from SD-809) were increased in all subjects compared with (?+?)-HTBZ (from TBZ). Deuteration increased the half-life (8.6 vs. 4.8 hours), AUCinf (542 vs. 261 ng[bull]hr/mL) and, to a lesser extent, Cmax (74.6 vs. 61.6 ng/mL) of deuterated vs. non-deuterated (?+?)-HTBZ, respectively. Deuteration affected ?- and ?-HTBZ similarly. The AUCinf of deuterated O-desmethyl HTBZ metabolites were reduced by approximately half. Single doses of SD-809 and tetrabenazine were well tolerated and had a comparable safety profile.

Conclusions CONCLUSIONS: Deuteration of TBZ resulted in a more than two-fold increase in systemic exposure to total (?+?)-HTBZ, a near doubling of half-life and only minor increases in Cmax. The increased half-life of total (?+?)-HTBZ allows for administration of lower doses of SD-809 compared with TBZ, thus permitting comparable plasma exposure with lower peak and higher trough concentrations.

Authors/Disclosures
David A. Stamler, MD (Alterity Therapeutics) PRESENTER	Dr. Stamler has received personal compensation for serving as an employee of Alterity Therapeutics. Dr. Stamler has stock in Alterity Therapeutics.
	No disclosure on file
Mehran Kavoosi	No disclosure on file
	No disclosure on file

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