In vivo characterization of Perseris and compositionally equivalent formulations

Abstract

Perseris is asubcutaneous extended-release risperidone in situ forming implant (suspension) indicated for the treatment of adult schizophrenia. Owing to the release rate controlling polymer poly(lactide-co-glycolide) (PLGA), one injection of Perseris can deliver risperidone for one month, which significantly reduces the administration frequency and improves patient compliance. The PLGA and drug used in Perseris was previously identified through reverse engineering and two compositionally equivalent formulations (F-1 and F-2) showing similar in vitro drug release were developed. The current work focuses on in vivo exploration of Perseris and the developed compositionally equivalent formulations using a rabbit model and further evaluate the sameness of the developed formulations compared to Perseris. The in vivo pharmacokinetic (PK) profiles, drug absorption rate, phase separation rate, macro appearance, weight loss as well as the water uptake of the solidified drug depots at different time points were investigated and compared with the in vitro release data as well as with dog and human in vivo data available in literature. Results show that the rabbit PK profile of Perseris was relevant with those obtained from both the dog model and the clinical data, indicating that the rabbit model is appropriate for investigation of the in vivo performance of risperidone implants. Consistent with their similar in vitro drug release, the two compositionally equivalent formulations demonstrated similar PK profiles, drug absorption rates, weight loss and swelling in vivo compared to Perseris. Although the erosion mechanism appeared to be similar between in vitro and in vivo, there were in vitro-in vivo differences concerning the drug release kinetics, phase separation rates and swelling behavior. This work provides a comprehensive in vitro/in vivo understanding of Perseris and the developed compositionally equivalent formulations, which will be beneficial for future development of generic as well as novel PLGA in situ forming implant products.