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Aims: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL 40 ), and several covariates using all data from five clinical studies., Methods: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL 40 ., Results: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL 40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data., Conclusions: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg., (© 2024 Laboratorios Farmaceuticos ROVI S.A. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted., Methods: Eligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales., Results: Altogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed., Conclusion: Risperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone., (Copyright © 2021 Laboratorios Farmacéuticos Rovi, S.A. Published by Elsevier B.V. All rights reserved.)

Introduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM ® ) and oral risperidone in patients stabilized on oral risperidone treatment., Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized., Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (C min, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUC tau) , maximum plasma concentration at steady-state (C max, ss) and average plasma concentration (C ave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone., Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses., Competing Interests: Lourdes Anta, Lourdes Ochoa, Ignacio Ayani, Javier Martínez and Ibon Gutierro are employees of Laboratorios Farmacéuticos Rovi, S.A., the sole developer of Risperidone ISM. Dr Javier Martínez also reports grants from Centro para el Desarrollo Tecnológico Industrial, during the conduct of the study. David P Walling has received grant funding from Novartis, Janssen, Intracellular, Lyndra, Rovi, Otsuka, Alkermes, Cerevel, AbbVie, Allergan, Noven, Takeda, Indivior, Avanir, Lundbeck, Roche, Boehringer Ingelheim, Biogen, Sunovion and Acadia. He has served on Advisory Boards for Otsuka, Janssen, Biogen, Boehringer Ingelheim and Lyndra. Howard A. Hassman declared that he has no competing interests. The authors report no other conflicts of interest in this work., (© 2021 Walling et al.)

This study characterized the pharmacokinetics, safety, and tolerability of Risperidone ISM, a new long-acting intramuscular formulation, for monthly administration without oral supplementation. Patients with schizophrenia received multiple intramuscular injections of 75 mg in the gluteal or deltoid muscle at 28-day intervals. Of the 70 randomized patients, 67 received at least one dose of study medication. The mean Cmax of the active moiety was achieved 24-48 h (tmax) after each administration, regardless of injection site. They ranged over four consecutive doses from 39.6 to 53.2 and 54.1 to 61 ng/ml, when given in gluteal or deltoid muscle, respectively. Active moiety achieved therapeutic levels by 2 h after dose, and the levels were maintained throughout the 4-week dosing period. No significant changes across the study were observed on either Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 (94%) patients experienced at least one treatment-emergent adverse event (TEAE). One serious TEAE (dystonia) was related to study treatment. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Risperidone ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-week dosing period over multiple intramuscular injections and was found to be safe and well tolerated.

The aim of this study was to characterize the pharmacokinetics and to evaluate the safety of risperidone ISM in patients with schizophrenia or schizoaffective disorder after a single gluteal intramuscular injection at three different dose strengths (50, 75, and 100 mg). A total of 36 patients were randomized and blood samples were collected to measure the plasma concentrations. The pharmacokinetic of the active moiety was biphasic for all three dose groups, and the mean plasma concentration was 21.45, 24.60, and 29.68 ng/ml in the 50, 75, and 100 mg group, respectively, 24 h after dose administration; 22.81, 24.57, and 31.41 ng/ml in the 50, 75, and 100 mg group, respectively, 48 h after dose administration, and 12.26, 17.31, and 20.01 ng/ml in the 50, 75, and 100 mg group, respectively, 30 days after dose administration. Overall, 34 patients experienced at least one treatment-emergent adverse event (TEAE). Two patients experienced a serious TEAE and no deaths occurred. There were no extrapyramidal symptoms-related serious TEAEs and no significant changes in any Columbia Suicide Severity Rating Scale parameter were observed during the study. Risperidone ISM provided a sustained release of risperidone that achieved therapeutic plasma levels within the first day. Risperidone ISM was safe, well tolerated, and should be suitable for a 4-weekly administration without oral supplementation.

Robert Litman,1,2 Dieter Naber,3 Lourdes Anta,4 Javier Martínez,4 Yuriy Filts,5 Christoph U Correll6– 8 1CBH Health LLC, Gaithersburg, MD, USA; 2Department of Psychiatry, Georgetown University Medical School, Washington, DC, USA; 3Department of Psychiatry and Psychotherapy, Hamburg-Eppendorf University, Hamburg, Germany; 4Medical Department, Laboratorios Farmacéuticos ROVI, S.A., Madrid, Spain; 5Communal Noncommercial Enterprise of Lviv Regional Council, Lviv Regional Clinical Psychiatric Hospital, Lviv, Ukraine; 6Department of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 7Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 8Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Javier Martínez, Laboratorios Farmacéuticos ROVI, S.A., Calle Alfonso Gómez, 45A, Madrid, 28037, Spain, Tel +34 91 375 63 36, Fax +34 91 304 78 81, Email jmartinez@rovi.esObjective: To analyze the effect of Risperidone ISM on social functioning and health-related quality of life (HR-QoL) in both short- and long-term treatment of patients with schizophrenia.Patients and Methods: This analysis was based on data from both phases of the PRISMA-3 study, including 433 relapsed patients from the double-blind (DB) phase of the PRISMA-3 trial who were treated for 12-weeks with once-monthly (every 28 days) intramuscular Risperidone ISM 75 mg or 100 mg (n = 288), or placebo (n = 145), as well as 174 patients transitioning from the DB to an open-label 52-week extension (OLE) phase, plus 41 de novo patients treated on a stable maintenance dose of oral risperidone. The clinician-administered Personal and Social Performance (PSP) scale and the patient-reported 20-item Subjective Well-being under Neuroleptics scale (SWN-20) were used to measure social functioning and HR-QoL outcomes, respectively.Results: Risperidone ISM significantly improved PSP total score from baseline to endpoint (Day 85) versus placebo in the DB phase with mean change total score (95% CI) of 10.7 (9; 12) compared to 4.8 (3; 7) for placebo (p < 0.0001). The statistically significant improvement was present from the first measurement time point (Day 29). SWN-20-measured HR-QoL increased on average in patients treated with Risperidone ISM in the DB phase. A significant improvement was also observed for PSP and SWN-20 scores from the OLE baseline to week 52 for patients transitioning from the DB phase. Stable de novo patients maintained similar PSP and SWN-20 scores during the whole OLE phase.Conclusion: Risperidone ISM provided a rapid and sustained improvement in personal and social functioning, and HR-QOL without need of oral risperidone supplementation or loading doses. These findings, along with a fast onset of efficacy, could contribute to reinforcing the therapeutic alliance and possibly an earlier discharge. Moreover, patient functioning continued improving or was maintained with long-term treatment.Keywords: risperidone, long-acting injectable, antipsychotics, schizophrenia, social functioning, quality of life

Walling DP, Hassman HA, Anta L, et al. Drug Des Devel Ther. 2021;15:4371–4382. Page 4378, Table 2, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. Page 4379, Table 3, PK Parameter column, the text “Cave (ng/nL)” should read “Cave (ng/mL)”. The authors apologize for the errors. Read the original article

Introduction Risperidone-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 C max between 7.5 ng/mL and 80 ng/mL. Aim Use 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. Methods A 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. Results Doses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median C max and C trough 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. Conclusions Simulations 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. [ABSTRACT FROM AUTHOR]

Introduction Risperidone-ISM is a new long acting intramuscular formulation of risperidone, for monthly administration without oral supplementation. Objective To characterize the pharmacokinetic of risperidone over multiple intramuscular injections in patients with schizophrenia. Method A multicenter, open label, two-arm, parallel design clinical trial was performed. Each patient received 4 intramuscular injections of 75 mg of risperidone-ISM in either, gluteal or deltoid muscle at 28-day intervals. Results A total of 70 patients were randomized, 67 received at least one dose of study medication. Preliminary data show that mean C max of the active moiety was achieved 24-48 hours (T max ) after each administration and ranged over four consecutive doses from 39.6-53.2 ng/mL and 54.1-61 ng/mL, when given in gluteal or deltoid, respectively. All subjects achieved therapeutic levels (> 7.5 ng/mL for the active moiety) between 2-8 hours after drug administration. The mean concentrations were maintained above therapeutic levels throughout the 4-week dosing period. No significance changes across the study were observed, either on Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 subjects (94%) experienced at least 1 Treatment Emergent Adverse Event (TEAE) during the study. One serious TEAE (dystonia) was related to study treatment. One death not related to study medication was informed. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Conclusions Risperidone-ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-weeks dosing period over multiple intramuscular injections independently of the injection site. Risperidone-ISM was found to be safe and well tolerated. [ABSTRACT FROM AUTHOR]