(T1230-10-63) TV-46000, a Novel Long Acting Injectable (LAI) Formulation of Risperidone, Forms a Stable and Robust Subcutaneous Depot, Even under Extreme Conditions: Prediction from Dog and Minipig to Human

Purpose: To evaluate the effect of heating and rubbing, directed on the site of injection, on risperidone total active moiety (TAM) pharmacokinetic (PK) profile, following TV-46000 (risperidone for extended-release subcutaneous injectable suspension) administration.

Methods: TV-46000 sc depot formation and stability was demonstrated in vivo by applying extrinsic factors such as heating and rubbing of the drug injection site at several time-points post-dose, and monitoring PK and safety profiles in animals. The validity of the finding in animals was confirmed in the clinics, comparing the PK of the sum of risperidone and its active metabolite (TAM) with and without massaging of the injection site. Male Gottingen minipigs were injected with a single 50 mg sc dose of TV-46000. After administration, 8 minipigs underwent injection-site heating to 40-42°C for 20 minutes at: 2h, 24h, 72h, 120h, 168h post-dose. Under a separate protocol, 3-4 minipigs were subjected to rubbing of the injection-site at either: 1h, 2h, 3h, 6h post- dose or at 24h, 48h and 72h post-dose, for 1 minute each time. Massage was applied using the lateral side of a 10-cc syringe, rolling over the marked injection-site for 1 minute with at least 30 back-and-forth rolls. Additional animals served as control where their injection-site was not rubbed nor heated. Risperidone and its active metabolite plasma levels were quantified prior and after each heating or rubbing treatment and up to 30 days post-dose. The effect of rubbing was further evaluated in a pilot clinical study in healthy volunteers where 10 subjects receiving a single 12.5 mg TV-46000 sc dose were subjected to injection-site massage immediately after sc injection and compared to 9 subjects receiving the same dose with no manipulation of injection-site. Five groups of male naïve beagle dogs (n=6/group), were treated with single sc injections of TV-46000 to replicate the pilot clinical study in healthy volunteers, and to provide additional timepoint to characterized the depot solidifying and therefore TV-46000 was given to dogs at similar dose level (12.5mg), and the same rubbing technique and duration were applied as in the clinical study. Groups 2, 3, 4, and 5 were rubbed at 0, 0.5, 1 or 4h post-injection. No rubbing was applied to group 1. The injection site was rubbed applying moderate pressure in back and forth motions with the palmar surface of gloved fingers by the administrator, for 30s (±5s).

Results: Through all studies, heating or rubbing of injection site at all the tested times post injection was well tolerated and no local adverse reactions were observed. In minipig studies, release of risperidone, and its related PK profile was not affected by heating 2-168h post dose, nor rubbing 1-72h post dose. TAM peak concentration was observed at 2-3h post-injections for all groups, regardless of heating or rubbing sessions. No bursts or uncontrolled release were observed. Plasma concentration of the TAM after each heating or rubbing session was compared to the plasma levels of same animals just prior to the injection site heating/rubbing, showing similar levels. Moreover, a similar concentration-time profile was achieved from all treatment groups indicating that heating or rubbing had no effect on risperidone release, retaining similar release profile and similar exposure (Figures 1 and 2). In dogs, immediate rubbing of the site of injection still allowed the depot to form and control the release of the drug with only slight increase in exposure of TAM. The relative exposure for dose-normalized C_max and AUC_0-t were 123%, and 133%, respectively, as compared to control group with no rubbing. Rubbing at different times from 0.5- 4h post-injection did not cause an increase in risperidone, active metabolite or TAM exposure in dogs (Figure 2). This increase in exposure appears consistent with results obtained in the pilot clinical study, in which rubbing immediately post-injection resulted in similar increase in C_max and AUC values. Furthermore, same as in the animals, the impact of manipulation of the injection site in humans as compared to the same dose conditions administered minus manipulation had no clinically meaning impact on the safety profile.

Conclusion: These investigations showed that rubbing of TV-46000 sc injection site immediately post-injection still allowed the depot to form and release risperidone in a controlled manner, although some changes in PK characteristics were evident. Manipulation (Rubbing or heating) after the depot is formed (≥0.5h post-injection) in the animals had no effect on TAM exposure, concluding the formed depot appears to be stable and robust. Additionally, rubbing and heat application on the site of injection following TV-46000 sc administration did not result in any safety concern. The observed similarity between dog and human rubbing results supports the translatability from animal models to clinical setting with regards to exploring the effects of extrinsic factors.

Risperidone TAM concentration time with and without heating following 50mg TV-46000 sc dose in minipigs (n=8/group)

Risperidone TAM concentration time with and without rubbing following 12.5mg TV-46000 sc dose in beagle dogs (n=6/group)