Abstract Details

Title Assessment of Dose Proportionality of Three Dose Strengths (6 mg, 12 mg and 24 mg) over the Clinical Dose Range (6-48 mg) of the Newly Developed Once-Daily Extended Release Tablet Formulation of Deutetrabenazine

Topic Movement Disorders

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 5-016

Objective To assess dose proportionality of three dose strengths (6mg, 12mg and 24mg), and across recommended clinical dose range (6mg – 48mg), for the once-daily (QD) extended-release tablet formulation of deutetrabenazine.

Background

Deutetrabenazine (Austedo, Teva), a twice-daily (BID) formulation, is an approved treatment (daily doses 6-48mg) for tardive dyskinesia and chorea associated with Huntington disease. The new QD formulation has shown to deliver similar daily exposure to the BID formulation.

Design/Methods In a randomized phase 1 study (Study TV50717-PK-10175), healthy adult males and females (n=116) received single administrations of the QD formulation in a fed state (2×6mg, 1×12mg, 1×24mg, 2×24mg). Safety was assessed, and pharmacokinetic (PK) blood samples were collected pre-dose and up to 96 hours post-dose. Geometric mean ratios (GMRs) and 90% CIs were computed for PK parameters (maximum plasma concentration[C_max], area under the plasma concentration curve from time 0 to 36 hours [AUC_0-36h]and extrapolated to infinity [AUC_0-inf]) of deutetrabenazine, and active metabolites, deuterated α-HTBZ and β-HTBZ (individually and as a sum). A power model was fitted to describe the relationship between dose and PK parameters using a mixed model with sequence, period, and dose as fixed effects; and subject as random effect. To determine dose proportionality starting at 6mg, relative bioavailability was assessed between 2x6mg and 1x12mg.

Results GMRs and 90% CIs for C_max and AUCs fell within the bioequivalence limits of 80.00%-125.00%, demonstrating similarity between 2x6mg and 1x12mg tablets. Dose proportionality was demonstrated for all PK parameters and all analytes for QD formulation dose strengths 6mg, 12mg, and 24mg; and over the clinical dose range (6-48mg), as the 90% CIs for the slopes were contained within 0.839 to 1.161 and 0.839 to 1.107, respectively.

Conclusions

The QD formulation of deutetrabenazine exhibits dose proportional pharmacokinetics for dose strengths (6mg, 12mg and 24mg), and across the full clinical dose range (6mg - 48mg).

Authors/Disclosures
Maria Sunzel, PhD (Teva Pharmaceuticals) PRESENTER	Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte.
Giulia Ghibellini, PhD	Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Mark F. Gordon, MD, FAAN (Teva Pharmaceuticals)	Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva.
Laura Rabinovich-Guilatt	No disclosure on file

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