# An Evaluation of the Subcutaneous Depot Release of TV-46000, A Novel Long-Acting Injectable (LAI) Formulation of Risperidone, Under Extreme Conditions in Dogs, Minipigs and Humans

## TL;DR

This study evaluated how manipulating the injection site of a long-acting antipsychotic drug affects its release in animals and humans, finding no significant impact on safety or drug levels.

## Contribution

The study demonstrates that heating or rubbing the injection site of TV-46000 does not cause uncontrolled drug release or safety issues.

## Key findings

- Heating or rubbing the injection site had no clinically meaningful impact on safety.
- No burst or uncontrolled release of the drug was observed after depot formation.
- Animal and human study results were consistent, supporting the use of animal models for such evaluations.

## Abstract

Background: TV-46000 (Uzedy, Teva), a long-acting subcutaneous antipsychotic, is an injectable formulation of risperidone and is approved by the FDA for the treatment of schizophrenia in adults. Its innovative copolymer-based drug delivery depot technology (licensed from MedinCell, Jacou, France) allows for plasma concentrations of the total active moiety of risperidone (TAM) to reach clinically relevant levels within 6–24 h and the maintenance of these therapeutic levels with monthly and bimonthly dosing regimens. Objective: As part of the development program for TV-46000, the effect of extrinsic factors of manipulation on the site of injection, and on the pharmacokinetic (PK) profile of TAM following TV-46000 administration was evaluated. Methods: Studies were conducted assessing the effect of heat and rubbing with male Gottingen minipigs and the effect of rubbing with male beagle dogs. A pilot clinical study in healthy volunteers was performed to evaluate the effect of rubbing. Results: These investigations showed that heating or rubbing of the TV-46000 sc injection site immediately post-injection had no clinically meaningful impact on safety and no burst or uncontrolled release was evident. Furthermore, no impact of injection site manipulation on TAM exposure was observed after depot formation (≥0.5 h post-injection). Conclusions: The observed similarity in findings between the animal and human studies supports the suitability of animal models for evaluation of the effect of extrinsic factors on injection sites and its translatability to clinical settings.