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
Eva-Maria Sunzel1, Giulia Ghibellini1, Malini Iyengar1, Maria Gutierrez1, Debra Ruffo1, Mark Forrest Gordon1, Laura Rabinovich-Guilatt1
1Teva Pharmaceutical Industries Ltd
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 [Cmax], area under the plasma concentration curve from time 0 to 36 hours [AUC0-36h] and extrapolated to infinity [AUC0-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 Cmax 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).