An Open-Label Study to Assess Monthly Risperidone Injections (180 mg) Following Switch from Daily Oral Risperidone (6 mg) in Stable Schizophrenic Patients

This open-label Phase 4 study was conducted between June 2019 and May 2020. We recruited patients with clinically stable schizophrenia [assessed using Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria] who were between 18 and 65 years old and were on a stable dose of 5 or 6 mg/day of oral risperidone. Any daily or twice-daily dosing combination (i.e., 3/3, 4/2, 3/2) was acceptable. Since risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6, which is subject to genetic polymorphism, only extensive CYP2D6 metabolizers were allowed to participate in the study based on CYP2D6 genotyping results from blood sampling at screening. Details on study inclusion/exclusion criteria are provided in Online Resource 1.

It was planned for 25 subjects to receive study drug treatment. The sample size was based on earlier clinical experience and pharmacokinetic knowledge and was expected to provide an adequate number of subjects (at least 15 evaluable) to assess the pharmacokinetic parameters of RBP-7000 as well as oral risperidone. All participants provided written informed consent before screening procedures. The study was approved by the local ethics committee and was registered at ClinicalTrials.gov (identifier: NCT03978832).

Eligible participants who met the screening criteria were first stabilized on 6 mg/day of oral risperidone given as 3 mg twice daily (BID)] 12 h apart for 5 days (Day −5 to− Day −1). Those who completed the stabilization period received up to 4 doses of 180 mg RBP-7000 every 28 days (on Days 1, 29, 57, and 85); each 180 mg dose was administered as 2, 90-mg SC injections. The first 3 doses were administered in the abdominal region (the 2 injections of 90 mg were administered in different quadrants of the abdomen, and injection sites were rotated between doses to minimize irritation). The fourth dose of 180 mg was administered in the back of the upper arm (participants received 1 injection of 90 mg in each arm).

The safety data from five participants following the first dose of 180 mg RBP-7000 were reviewed prior to continuation of the remaining study. At the end-of-study (EOS) visit, participants were evaluated and prescribed an appropriate maintenance antipsychotic at a dosage determined by the physician. The study design is depicted in Online Resource 2.

Blood samples for the determination of risperidone and 9-hydroxyrisperidone plasma concentrations were collected during oral risperidone stabilization period (Day −5–Day −2: prior to the morning dose; Day −1: prior to and at 0.5, 1, 2, 4, 6, and 12 h after the morning dose) and after each SC injection of RBP-7000 [Doses 1 and 2: pre-dose and 2, 4, 6, 24, 48, 168, 240, 336, 408, 504, and 576 h post-dose; Doses 3 and 4: same schedule with additional samples at 12, 120, 192, 216, 288, and 672 h (Dose 4 only)]. The additional blood samples taken after Doses 3 and 4 of RBP-7000 were collected for a more accurate calculation of RBP-7000 pharmacokinetic parameters at steady-state. Approximately 6 mL of blood was collected at each time point into pre-labelled vacutainer tubes containing ethylenediaminetetraacetic acid (K₂-EDTA). Blood sampling was performed by appropriately qualified and trained study personnel, either by individual venipuncture or through an inserted indwelling catheter with a saline lock in the subject’s forearm to minimize subject’s risk and discomfort.

Adverse events (AEs) were monitored and reported by the investigator or designee throughout the study until the follow-up telephone call on Day 120. All clinically significant symptoms were reported as AEs, and all AEs and corresponding treatment were recorded in the database. The World Health Organization’s Uppsala Monitoring Centre (WHO-UMC) causality assessment was used to define the relationship of an AE to the administration of RBP-7000. Clinical assessments for safety included the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia [21], the Simpson-Angus Scale (SAS) [22], the Barnes Akathisia Rating Scale (BARS) [23], and the Columbia-Suicide Severity Rating Scale (C-SSRS) [24]. AIMS, SAS, and BARS evaluations were conducted at screening, on Day −1, and on Days 2, 8, 15, 22, 29, 50, 57, 85, and 113. C-SSRS assessments were performed at screening, on Day −1, and on Days 8, 15, 36, 57, 64, 78, 94, and 113. Additional safety and tolerability evaluations included injection site pain [using a patient-reported 100 mm Visual Analog Scale (VAS)] and injection site tolerability gradings measured after each injection, as well as vital signs, changes in clinical laboratory results, physical examinations, and 12-lead electrocardiograms (ECG).

Efficacy evaluations were conducted at screening, on Day −1, and on Days 2, 8, 15, 22, 29, 50, 57, 85, and 113 following administration of RBP-7000. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) [25] and the Clinical Global Impression Scale for Severity of Illness (CGI-S) [21].

Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated method of liquid chromatography with tandem mass spectrometry (LC–MS/MS). The analytical methodology was based on the following procedure: 0.05 mL of human plasma containing internal standards (d4-risperidone, d4-9-hydroxyrisperidone) was first acidified and then extracted using solid-phase extraction. Analysis required evaporation of elute solvent before being reconstituted. An aliquot of the extract was injected onto a Sciex API 5500 LC–MS/MS equipped with a high-performance liquid chromatography column. Quantitation was performed using 1/x² weighted linear least squares regression analysis generated from fortified plasma calibration standards prepared immediately prior to each run. The method was validated for specificity, linearity, lower limit of quantitation, precision, accuracy, recovery, and stability for a range of 0.1–100 ng/mL for both analytes. The overall precision for risperidone and 9-hydroxyrisperidone was greater than 11.7%; the overall accuracy was within ± 4.4%. The recoveries of both analytes and internal standards were greater than 91%. The established short-term and long-term stability covered the maximum sample storage time.

The total active moiety plasma concentration was calculated as the sum of risperidone and 9-hydroxyrisperidone plasma concentrations after correction for their molecular weights (410 for risperidone and 426 for 9-hydroxyrisperidone) according to the following formula: [active moiety] = [risperidone] + [9‐hydroxyrisperidone] × (410/426).

Non-compartmental pharmacokinetic analyses were performed on the pharmacokinetic population, defined as participants who received oral risperidone or at least 1 dose of RBP-7000 and who provided an adequate number of blood samples for determination of pharmacokinetic parameters (N = 24). The primary endpoint for the study was the steady-state average plasma concentration (C_avg(ss)) of risperidone and total active moiety measured after administration of oral risperidone (Day −1) and RBP-7000 (Dose 3). Secondary pharmacokinetic parameters included maximum plasma concentration at steady-state (C_max(ss)), minimum plasma concentration at steady-state (C_min(ss)), and percent fluctuation calculated as (C_max(ss) – C_min(ss))/C_avg(ss) × 100. Steady-state attainment after oral and SC dosing was evaluated using descriptive summary statistics of plasma concentrations. For the primary analysis (comparison of RBP-7000 Dose 3 versus oral risperidone), only the data from those participants who received all 3 doses of RBP-7000 and provided an adequate number of blood samples for the determination of C_avg(ss) were considered (N = 16). Mean plasma concentration-time profiles and pharmacokinetic parameters determined after the fourth RBP-7000 dose (alternate site, back of upper arm) were compared with those obtained after the third RBP-7000 dose (abdominal site) for risperidone, 9-hydroxyrisperidone, and total active moiety. Pharmacokinetic parameter comparisons were done using geometric mean ratios (GMRs) with 90% confidence intervals (CIs) derived from random effects models, with the logarithm of the pharmacokinetic parameter value as the dependent variable, dose number as the independent variable, and subject as a random effect.

Additional secondary endpoints were safety and tolerability of the RBP-7000 injections, which were ascertained in participants who had received at least one dose of RBP-7000 (safety population; N = 23). Secondary endpoints for efficacy were the change from baseline in PANSS subscale scores and CGI-S score. These endpoints were summarized for the efficacy population (N = 23) defined as participants who received at least 1 dose of RBP-7000 and had at least one post-dose efficacy observation.

All statistical analyses were performed using SAS^® software version 9.4 (SAS Institute, Inc., Cary, NC, USA). WinNonlin Phoenix version 6.3 (Pharsight Corporation) was used for pharmacokinetic parameter calculation.

The disposition of study participants is shown in Fig. 1. In all, 25 of the 69 screened participants received oral risperidone during the stabilization period, 23 received at least 1 dose of RBP-7000, 16 received all 4 doses of RBP-7000, and 15 completed the study. One participant received all 4 SC doses but was lost to follow-up prior to EOS procedures.

Demographic and baseline characteristics for the safety and pharmacokinetic populations were similar based on descriptive statistics (Table 1). The majority of participants were male, and age ranged from 26 to 65 years. Nearly three-quarters were Black or African American, with whites comprising the next highest race (approximately 21%); 13% were of Hispanic or Latino ethnicity. Body mass index (BMI) ranged from 19.6 to 34.8 kg/m².

The mean pharmacokinetic profile for the total active moiety throughout the study is presented in Fig. 2A. Data show that steady-state for RBP-7000 was achieved by the end of the second dosing interval, while plasma concentrations close to steady-state were attained after the first dose of RBP-7000. Steady-state pharmacokinetic parameters of risperidone, 9-hydroxyrisperidone, and total active moiety are summarized in Table 2 for oral risperidone (Day −1) and RBP-7000 for Dose 3 (abdominal site) and Dose 4 (upper arm). Table 2 also presents GMRs with their 90% CIs for comparison of pharmacokinetic parameters between oral risperidone and RBP-7000 on one hand and between the two injection sites on the other hand.

Results show that similar C_avg(ss) of the total active moiety was achieved after 3 monthly doses of 180 mg RBP-7000 compared with 6 mg/day of oral risperidone (3 mg BID), with geometric means of 44.05 ng/mL and 43.73 ng/mL, respectively (GMR [90% CI]: 1.01 [0.91, 1.12]). For risperidone, C_avg(ss) was higher following the third dose of RBP-7000 compared with oral risperidone (GMR [90% CI]: 1.98 [1.54, 2.55]). This was largely due to two participants whose risperidone C_avg(ss) values were higher but their corresponding 9-hydroxyrisperidone levels were lower, resulting in similar C_avg(ss) values for the total active moiety.

On the basis of geometric means, risperidone and total active moiety C_max(ss) appeared slightly higher after RBP-7000 administration compared with oral risperidone, although the 90% CI for GMR included 1. Risperidone C_min(ss) was higher after RBP-7000 administration (GMR [90% CI]: 4.02 [3.03, 5.33]), while total active moiety C_min(ss) was higher after oral administration (GMR [90% CI]: 0.70 [0.62, 0.80]). The percent fluctuation for RBP-7000 was lower than for risperidone (135% versus 252% for oral dosing), but slightly higher for total active moiety (106% versus 68% for oral dosing) based on geometric mean data.

Administration of RBP-7000 at an alternate injection site (back of upper arm) provided comparable pharmacokinetic profile (Fig. 3) and similar plasma exposure (C_avg(ss)) of total active moiety compared with injection in the abdominal region (Table 2). Geometric means for C_avg(ss) were 43.73 ng/mL following injection in the upper arm compared with 44.05 ng/mL following injection in the abdomen (GMR [90% CI]: 0.99 [0.92, 1.07]). Other pharmacokinetic parameters were similar between the two injection sites with GMRs close to 1 (1.09 for C_max(ss) and 1.00 for C_min(ss)).

Overall, 69.6% (16 of 23) of participants had 1 or more treatment-emergent adverse event (TEAE) during the study (Online Resource 3) and 26.1% (6 of 23) of participants had TEAEs assessed by the investigator as related to study drug (Online Resource 4). The most common TEAEs were upper respiratory tract infection [number of events (n) = 3], blood prolactin increased (n = 2), decreased appetite (n = 2), dyskinesia (n = 2), fall (n = 2), and headache (n = 2). The most frequently reported system organ class included nervous system disorders (five participants, 21.7%); four participants had five TEAEs associated with extrapyramidal symptoms [akathisia (n = 1), dyskinesia (n = 2), Parkinsonian gait (n = 1), tremor (n = 1)]. Most TEAEs during the study were of mild severity (25 events in 11 participants, 47.8%) or moderate severity (5 events in 4 participants, 17.4%). There was one participant with a severe TEAE (tooth extraction) and one study treatment discontinuation due to a TEAE (Parkinson’s gait). There were no participants with serious adverse events (SAEs) reported during the study; however, there was one SAE that occurred after study completion (Day 133). This SAE was an increase in liver enzymes, which was considered moderate in severity and unrelated to study treatment. There were no deaths in the study.

In general, there were no clinically meaningful differences in the pattern of injection site gradings following the first dose compared with subsequent doses of RBP-7000. Injection site pain, tenderness, erythema/redness, and induration/swelling grades were graded as none in the vast majority of cases. In the few cases that reported a reaction, these cases were graded as mild in severity. Injection site burning/stinging decreased within 1 h after each dose in most participants. Participant reports of injection site pain on a VAS were generally on the lower end of the scale, with no clinically meaningful differences between doses (Online Resource 5). After each dose, injection site pain scores decreased within 1 h in most participants. Overall, injection-site tolerability assessments revealed no clinically meaningful differences between the two injection sites, and all injections were considered well tolerated.

Analyses of vital signs, AIMS, SAS, BARS, C-SSRS, and ECG assessments and clinical laboratory evaluations did not reveal any clinically relevant effect of RBP-7000 treatment.

Mean (± SD) changes from baseline for PANSS total score at each data collection point are shown in Fig. 2B. Overall, the PANSS mean and individual total scores remained stable throughout the study, as did all PANSS subscale (positive, negative, and general psychopathology) mean scores. Figure 2C displays the mean (± SD) change from baseline for the CGI-S observed scores at each timepoint. As seen with the PANSS data, CGI-S scores remained stable throughout the study; mean observed values were identical at baseline (3.3 ± 0.45) and EOS (3.3 ± 0.73). There were no clinically meaningful differences in mean scores by dose or between the two injection sites (Dose 3 and Dose 4). Tables summarizing observed scores and changes from baseline by visit are provided in Online Resource 6 for PANSS total score and Online Resource 7 for CGI-S.

Monthly injections of 180 mg RBP-7000 administered as 2 SC injections of 90 mg provided similar average plasma concentration of the total active moiety compared with 6 mg/day oral risperidone given as 3 mg BID. These data combined with the stable clinical efficacy measures support the conclusion that RBP-7000 180 mg dose approximates 6 mg/day oral risperidone. The administration of 180 mg RBP-7000 at the back of the upper arm showed comparable pharmacokinetic profiles to RBP-7000 administration in the abdomen with no clinically meaningful differences in safety or efficacy measures, supporting its use as an alternate injection site. Overall, the safety profile was consistent with the established safety profile of RBP-7000 (90 and 120 mg dosage strengths) and other risperidone products. On the basis of these findings, 180 mg RBP-7000 should be considered an option for patients with schizophrenia who would benefit from switching from 5 to 6 mg/day oral risperidone.