Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

Abstract

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.