30. ONCE -DAILY VALBENAZINE FOR TARDIVE DYSKINESIA OR HUNTINGTON’S DISEASE CHOREA IN PATIENTS WITH DYSPHAGIA

Introduction

Valbenazine (VBZ) is a unique once-daily medication approved for tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD). For patients with TD and HD, swallowing whole pills may be difficult due to their motor symptoms, advanced age, or other comorbid conditions. Alternative modes for medication administration are therefore needed. In vitro studies with 2 approved VBZ formulations assessed the following: suitability of crushing the contents of INGREZZA® capsules (compacted, consolidated powder plug) for mixing with soft foods or liquids and potential of delivering crushed capsule contents via gastrostomy tube (G-tube); and compatibility of INGREZZA® SPRINKLE capsules (new and recently approved VBZ granules formulation) with soft foods. A Phase 1 trial in healthy adults determined the bioequivalence between VBZ granules and the powder-plug capsule, and between fed and fasted states for VBZ granules.

Methods

The dissolution profile of VBZ crushed capsule contents (compact powder-plug formulation) was analyzed (Study 1), and VBZ recovery was evaluated when the crushed powder was mixed with soft foods and liquids (Study 2) or dispersed in water and delivered via G-tube (Study 3). VBZ recovery was also evaluated for uncrushed VBZ granules mixed with soft foods (Study 4). Acceptability was defined as VBZ recovery of 90-110% (Studies 2/3) or 95-105% (Study 4). A Phase 1 trial (Study 5) used a 3-sequence, 3-period crossover design to assess bioequivalence between the VBZ granules (taken as intact capsule or sprinkled on applesauce) and the intact VBZ powder-plug capsule (Cohort 1). A 2-sequence, 2-period crossover design was used to assess bioequivalence between fed and fasted states for VBZ granules sprinkled on applesauce (Cohort 2). Geometric mean ratios (GMRs) for Cmax and AUC of VBZ and its primary metabolite, [+]-α-dihydroxytetrabenazine ([+]-α-HTBZ), were analyzed for each test condition, with bioequivalence defined as the GMR 90% CI falling within 80-125%.

Results

Studies 1-3 indicated rapid and complete dissolution of crushed powder-plug contents of VBZ capsules (similar to intact capsules) and acceptable VBZ recovery when the crushed contents were added to foods and liquids with a wide pH range or delivered in water via G-tube. Study 4 showed VBZ granules to be compatible with various acidic and non-acidic foods. Study 5 indicated bioequivalence between VBZ granules (intact capsule or sprinkled on applesauce) and the VBZ powder-plug capsule (Cohort 1), with a slight delay in absorption rate of VBZ granules on applesauce (VBZ Cmax) but no effect on overall absorption (VBZ and [+]-α-HTBZ AUC). Bioequivalence between fed and fasted states was demonstrated for VBZ granules (Cohort 2).

Conclusions

Results from in vitro studies and a Phase 1 trial indicate that with 2 approved and available formulations, VBZ offers alternative modes of administration that are suitable for patients with dysphagia, including delivery of crushed VBZ capsules contents via G-tube or mixing VBZ granules into soft foods.