Population Pharmacokinetic Modeling of TV-46000, a Risperidone Long-Acting Subcutaneous Antipsychotic for the Treatment of Patients with Schizophrenia.

INTRODUCTION

TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) agent that combines risperidone and an innovative, copolymer-based drug delivery technology in a suspension suitable for subcutaneous administration from a prefilled syringe. The objective of the current analysis was to characterize the pharmacokinetics (PK) of TV-46000 based on pooled data from phase 1 and phase 3 studies, and to further support clinical use aspects of TV-46000.

METHODS

A population PK (popPK) model was developed using TV-46000 PK data obtained from three phase 1 studies (n = 267) and two phase 3 trials (n = 425). A sequential parent-metabolite model structure was used, and the total active moiety (TAM) concentration-time profiles were simulated for TV-46000 once monthly (q1m) and once every 2 months (q2m) across the range of available doses and different administration sites.

RESULTS

The popPK model adequately characterized the PK of risperidone and its active metabolite. TV-46000 reaches therapeutic plasma TAM concentrations (≥ 10 ng/mL) within 24 h following first dose administration. Three months after initiation of TV-46000, 86% and 88% of steady-state TAM exposure were achieved for q1m and q2m, respectively, and steady state was fully attained by 6 months (i.e., > 90% of steady-state TAM exposure). In addition, simulated D2 receptor occupancy for TV-46000 was generally within the therapeutic window of 60-80% during both dosing intervals.

CONCLUSIONS

The developed popPK model, together with corresponding simulations, supports TV-46000 as a LASCA that offers flexible dosing intervals (q1m or q2m) and administration sites (abdomen or upper arm) and does not require oral supplementation or loading dose(s).