A Bioequivalence Comparison at Steady State between the Newly Developed Once-Daily Extended Release Tablet Formulation and the Approved Twice-Daily Tablet Formulation of Deutetrabenazine (P2-11.015)

Abstract

<h3>Objective:</h3> To assess the bioequivalence (BE) and relative bioavailability (BA) between a once-daily (QD) extended release formulation of deutetrabenazine and the approved twice-daily (BID) formulation at steady state under fed conditions. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva) in a BID formulation is an approved treatment for tardive dyskinesia and chorea associated with Huntington disease. A QD formulation has been developed. <h3>Design/Methods:</h3> In a phase 1 study (TV50717-BE-10179) using a randomized cross-over design, healthy adult males and females (n=262) received 24 mg QD formulation (test) as a once daily administration and 12 mg BID formulation (reference) as a twice daily administration, each for 7 days in fed state. Safety was assessed throughout the study and pharmacokinetic (PK) blood sampling occurred on days 4–7. Test-to-reference geometric mean ratios (GMRs) and 90%CIs for BE acceptance limits (80.00% to 125.00%) were computed for PK parameters (area under the plasma concentration curve over 24-hours at steady-state [AUC_0–24hr,ss] and maximum plasma concentration at steady-state [C_max,ss]) of deutetrabenazine, active metabolites, deuterated α-HTBZ and β-HTBZ, and total (α+β)-HTBZ. Relative BA was assessed for C_max,ss of the active metabolites (individually and as a total sum). <h3>Results:</h3> The GMRs (90%CIs) for AUC_0–24hr,ss were 115.15% (110.38–120.14%) for deutetrabenazine, 95.40% (94.13–96.69%) for α-HTBZ, 94.13% (92.35–95.94%) for β-HTBZ, and 95.05% (93.67–96.46%) for total (α+β)-HTBZ. GMRs of C_max,ss were 95.09% (90.60–99.80%) for deutetrabenazine, 79.56% (78.21–80.94%) for α-HTBZ, 74.85% (73.13–76.60%) for β-HTBZ and 77.71% (76.26–79.16%) for total (α+β)-HTBZ. No new safety findings emerged in this study. <h3>Conclusions:</h3> At steady state, deutetrabenazine administered as the QD formulation was bioequivalent to the approved BID formulation for both AUC and C_max. The active metabolites at steady state were bioequivalent with regard to AUC between the QD and BID formulation; C_max was slightly lower for the QD formulation compared to the BID formulation. <b>Disclosure:</b> 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. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gutierrez has stock in Teva. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.