Summary

• The clinical trial program for INVEGA SUSTENNA and population pharmacokinetic (PK) model determined that patients with a higher body mass index (BMI ≥25 kg/m²) had a lower median paliperidone plasma concentration than patients with a normal BMI (<25 kg/m²) after the initiation of INVEGA SUSTENNA (prior to day 36).^1,2
• A lower initial plasma concentration in patients with high BMI is likely due to unintended partial or complete injections into adipose tissue. The hypovascularity of subcutaneous adipose tissue as compared with muscle tissue may result in a slower uptake of paliperidone from the gluteal muscle than is seen following deltoid muscle injections.^2,3
• Population PK modeling data have shown that injections of INVEGA SUSTENNA into the deltoid muscle resulted in a 37% higher fraction of paliperidone in the systemic circulation than is seen with injections in the gluteal muscle.^1,2
• Population PK simulations have suggested that the impact of BMI on paliperidone plasma concentrations may be mitigated by administering the day 1 (234 mg) and day 8 (156 mg) intramuscular (IM) injections in the deltoid muscle with a 1½-inch needle in patients ≥90 kg and a 1-inch needle in patients <90 kg,^1,4 which was confirmed in a subsequent clinical trial.^1,4,5
• Clinical studies and PK simulations suggest that, once steady state concentrations were achieved, no clear relationship between plasma paliperidone concentrations and BMI was observed.^2,6
• In a retrospective analysis of paliperidone plasma concentrations in obese, overweight, and normal patients receiving INVEGA SUSTENNA, no significant difference in steady state plasma concentrations were reported and BMI or body weight did not correlate with paliperidone plasma concentration or dose-adjusted plasma concentration (C/D).⁷
• The recommended needle size for administration of INVEGA SUSTENNA into the deltoid muscle is determined by the patient’s weight. For those ≥90 kg, the 1½-inch, 22 gauge needle is recommended. For those <90 kg, the 1-inch, 23 gauge needle is recommended. The recommended needle size for administration of INVEGA SUSTENNA into the gluteal muscle is the 1½-inch, 22 gauge needle, regardless of weight.³
• A post hoc analysis of a long-term multiphase clinical study showed that the highest incidence of metabolic-related treatment-emergent adverse events (TEAEs) occurred in obese patients, compared to patients classified as underweight, normal weight, or overweight; however, there was no trend for increased metabolic-related lab values based on BMI.⁸

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release (ER) injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

CLINICAL STUDIES

Initiation and Maintenance Dosing Strategies

Samtani et al (2009)^1,2,4,6 evaluated the optimal initiation and maintenance dosing strategies for INVEGA SUSTENNA with a population PK simulation model. The model was based on pooled data of 1,795 patients with schizophrenia and 18,530 PK samples with valid concentration time points.

Study Design/Methods

• Simulation was developed with a 1-compartment disposition model with a zero/first order absorption profile, which best described the PK of INVEGA SUSTENNA.
• The absorption component of the model allowed for a fraction of the dose to enter the central compartment relatively quickly through a zero-order process.
• After a certain lag time, the remaining fraction entered the systemic circulation through a first-order process that determined the shape of the plasma concentration-time curve following injection.
• PK profiles for 5,000 patients were simulated after INVEGA SUSTENNA injections were given on days 1, 8, and 36 and every 4 weeks thereafter.  Paliperidone plasma concentrations over 53 weeks were simulated on the basis of final estimates of the population PK model.
• To evaluate the outcome of simulations, the population median and 90% prediction intervals of simulated plasma concentration versus time profiles after multiple doses were displayed graphically.

Initiation Dosing Regimen

• Analysis was conducted to identify an optimal dosing strategy for the initiation of treatment with INVEGA SUSTENNA in adult patients with schizophrenia with a population PK simulation model and data from clinical trials. The initiation strategy was chosen to meet the following parameters:
  • By the end of 1 week after the first dose, paliperidone plasma concentrations must exceed the target threshold of 7.5 ng/mL. This concentration corresponds to a central D₂-receptor occupancy of approximately 60% (occupancy of 60%-80% is generally required for antipsychotic efficacy).
  • On days 8 and 36, paliperidone plasma concentrations must remain within the concentration window (3.5-50.0 ng/mL). The concentration window was based on the paliperidone ER phase III clinical trial program, where 90% of patient plasma concentrations resided within this window at the recommended dose of paliperidone ER 6 mg, which has been shown to be efficacious and well tolerated.
• Other assessments included the effect of BMI and needle length on INVEGA SUSTENNA dosing.

Maintenance Dosing Regimen

• An analysis was conducted to identify the optimal Maintenance Dosing Regimen for INVEGA SUSTENNA.

Results

Initiation Dosing Regimen

• The results of the population PK model indicated that injection of INVEGA SUSTENNA in the deltoid muscle provided a 37% higher fraction of paliperidone in the systemic circulation than did injection in the gluteal muscle.
• Simulation data 1 week after the initial dose of INVEGA SUSTENNA indicated that a greater percentage of patients achieved target paliperidone concentrations of >7.5 ng/mL after they received 234-mg deltoid injections than after they received 156-mg deltoid injections.  See Table: Percentage of Patients Achieving Paliperidone Concentrations >7.5 ng/mL at 1 Week After Initiating Treatment with Paliperidone Palmitate.

• Simulation data suggests that, after the initial dose of INVEGA SUSTENNA 234 mg on day 1 by deltoid administration, patients should receive a dose of INVEGA SUSTENNA 156 mg on day 8 through deltoid injection.
  • This regimen (234 mg on day 1, 156 mg on day 8, both administered in the deltoid muscle) rapidly achieves plasma paliperidone levels that are similar to those observed at steady state with the suggested monthly dose of INVEGA SUSTENNA 117 mg as well as the daily dose of paliperidone ER 6 mg at steady state (3.5-50 ng/mL).
• According to the population PK model and previous clinical trials, patients with a higher BMI (≥25 kg/m²) had a lower median paliperidone plasma concentration than those with a normal BMI (<25 kg/m²) after the initiation of INVEGA SUSTENNA (prior to day 36).
• Clinical trial data have indicated that a greater difference in paliperidone maximum plasma concentration (C_max) was observed when a 1½-inch versus a 1-inch needle was used to administer the IM injection in the deltoid versus gluteal muscle, and this was thought to be related to BMI.
  • Needle length was observed to be an important variable for the absorption kinetics from the deltoid injection site.
  • As a result, it is recommended that a longer 1½-inch needle be used for deltoid administration in heavier patients (≥90 kg). The use of a longer needle in the deltoid muscle for heavier patients might be associated with an initially faster release of paliperidone into the systemic circulation, which could help mitigate the slower absorption in this population.
• Simulation results also demonstrated that the initiation regimen (234 mg on day 1 and 156 mg on day 8, both administered in the deltoid muscle) appeared to substantially reduce the influence of BMI on the initial rising plasma concentrations for three out of the four BMI categories.
  • This was evidenced by higher percentages of subjects in the normal, overweight, and obese groups who achieved paliperidone plasma concentrations of >7.5 ng/mL at 1 week after initiation doses of 234 mg were given (see Table: Percentage of Patients Achieving Paliperidone Concentrations >7.5 ng/mL at 1 Week After Initiation of Treatment with Paliperidone Palmitate 234 mg [by BMI category]).

Maintenance Dosing Regimen

• Population PK simulations for monthly maintenance injections of INVEGA SUSTENNA 39, 78, and 156 mg, administered either in the deltoid or gluteal muscle, demonstrated that paliperidone plasma concentrations on day 36 and onwards were similar between patients who received deltoid injections and those who received gluteal injections.
  • This suggests that gluteal or deltoid injections of INVEGA SUSTENNA can be used interchangeably during maintenance treatment (see Figure: Similar Population Pharmacokinetic Simulations for Deltoid and Gluteal Muscle Injections During Maintenance Therapy).

Authors’ Conclusions

Initiation Dosing Regimen

• Clinical trial data and population PK simulations suggest that the effect of BMI on paliperidone plasma concentrations can be mitigated through administration of the day 1 (234 mg) and day 8 (156 mg) IM injections in the deltoid muscle with a 1½-inch needle in patients who weigh ≥90 kg and a 1-inch needle in patients who weigh <90 kg.

Maintenance Dosing Regimen

• Simulation results were supported by the results from one phase II and two phase III clinical studies that found that once steady state concentrations had been reached, there was no apparent relationship between plasma paliperidone concentrations and patient’s BMI.

Nonoptimized Dose Initiation Regimen

Fleischhacker et al (2011)⁹ compared efficacy and safety results between a clinical trial that used a nonoptimized dose initiation regimen of INVEGA SUSTENNA (n=749).

Study Design/Methods

• This was a 53-week, randomized, double-blind (DB), active-controlled, parallel-group, multicenter, comparative study designed to assess the noninferiority of INVEGA SUSTENNA (39, 78, 117, or 156 mg) to risperidone long-acting injection (25, 37.5, 50 mg) in adults with schizophrenia (n=747, safety analysis set).
• Patients assigned to INVEGA SUSTENNA (n=379) received IM gluteal injections of INVEGA SUSTENNA 78 mg on days 1 and 8, followed by flexible doses of INVEGA SUSTENNA 39, 78, 117, or 156 mg administered in the gluteal muscle every 4 weeks.
  • Patients received placebo injections every 2 weeks, as well as oral placebo supplementation during the first 4 weeks of treatment and for up to 3 weeks after every dose increase.
  • Dosage adjustments were allowed from week 5 onwards at 4-week intervals in 39-mg increments.
• Patients assigned to risperidone long-acting injection (n=370) received injections of placebo on day 1 and risperidone long-acting injection 25 mg on days 8 and 22, followed by flexible doses of risperidone long-acting injection 25, 37.5, or 50 mg administered every 2 weeks.
  • Patients also received oral supplementation with risperidone (1-6 mg/day) during the first 4 weeks of treatment and for up to 3 weeks after every dose increase.
  • Dosage adjustments were allowed from week 5 onwards at 4-week intervals in 12.5-mg increments.
• Tolerability testing was performed with oral paliperidone ER 3 mg for 4 days in those patients who had no previous exposure to oral risperidone, risperidone long-acting injection, or oral paliperidone ER.
• Primary efficacy assessment: change from baseline to end point with the last observation carried forward approach in the Positive and Negative Syndrome Scale (PANSS) total score. Noninferiority of INVEGA SUSTENNA to risperidone long-acting injection was to be concluded if the lower limit of the two-sided 95% confidence interval (CI) of the difference in the change in PANSS total score exceeded -5 points.

Results

• At endpoint, both INVEGA SUSTENNA and risperidone long-acting injection improved mean PANSS total scores from baseline (standard deviation): INVEGA SUSTENNA, -12 (21.2); risperidone long-acting injection, -14 (19.8).
• Least-squares means change in total PANSS score was 2.6 points lower (95% CI: -5.84, 0.61) for risperidone long-acting injection than for INVEGA SUSTENNA.  Since the lower bound of the 95% CI was -5.84, the predetermined margin for noninferiority (lower limit of the 95% CI) was not met.
• Overall plasma concentrations of paliperidone in the INVEGA SUSTENNA group were consistently lower than plasma concentrations of the active moiety (risperidone + 9-OH-risperidone/paliperidone) in the risperidone long-acting injection group.
  • Plasma concentrations of paliperidone palmitate until day 260 in patients who received gluteal injections of INVEGA SUSTENNA 78 mg were lower than active moiety levels in patients who received risperidone long-acting injection.
• These results suggested that the dosing regimen used for INVEGA SUSTENNA needs to be adjusted to optimize plasma concentrations.
• An exploratory analysis revealed an interaction between treatment and BMI that approached statistical significance (P=0.108) at the 10% level.  The point estimate (95% CI) for the difference in least-squares means between INVEGA SUSTENNA and risperidone long-acting injection indicated non-inferiority for the normal  (BMI <25 kg/m²) and overweight (BMI ≥25 to <30 kg/m²) subgroup was -0.5 (-4.01, 3.08), but not for obese patients (BMI ≥30 kg/m²) with -7.5 (-12.1, -2.82).

Authors’ Conclusions

• Overall, the efficacy and PK results from this trial showed that plasma concentrations in the INVEGA SUSTENNA group were lower than those in the risperidone long-acting injection group, probably because of suboptimal dosing and use of the gluteal initiation site.

Post Hoc Analysis - Metabolic Adverse Events

Sliwa et al (2014)⁸ conducted a post hoc analysis of Hough et al (2010)¹⁰ and Gopal et al (2011)¹¹ that evaluated the long-term effects of INVEGA SUSTENNA on metabolic adverse events (AEs).

Study Design/Methods

• Post hoc analysis of a study of INVEGA SUSTENNA that included a 9-week open-label transition (TR) phase, a 24-week open-label maintenance phases, a variable duration randomized, placebo-controlled, DB, relapse prevention phase, and an optional 52-week open-label extension (OLE) phase.
• In this analysis, patients who received INVEGA SUSTENNA continuously throughout the study were grouped according to baseline BMI:
  • Underweight (<19 kg/m²), n=29
  • Normal (19-<25 kg/m²), n=229
  • Overweight (25-<30 kg/m²), n=232
  • Obese ≥30 kg/m²), n=154

Results

Patient Characteristics

• 644 patients were included in the analysis, and 183 patients completed the OLE.
• The mean dose of INVEGA SUSTENNA was 109.6 mg, and the median duration of exposure was 204 days, and were similar across groups.

TEAEs (TR Baseline to OLE Endpoint)

• Patients experiencing ≥1 TEAE: 55% in the underweight group; >70% in the normal, overweight, and obese groups.
• At least 10% of patients in the normal, overweight, and obese groups experienced insomnia, anxiety, worsening of schizophrenia, and headache.
• Three deaths (2 in the normal group, 1 in the obese group) occurred and were reported by investigators as not related to study drug.
• Patients experiencing ≥1 metabolic TEAE: normal, 14.9%, overweight, 14.7%, obese, 24.0%.
• The most common (≥2%, any group) metabolic-related TEAEs in the underweight, normal, overweight, and obese groups were:
  • Weight increase: 0%, 11.4%, 7.3%, 11.7%, respectively
  • Blood glucose increased: 0%, 2.2%, 3.9%, 4.6%, respectively
  • Blood cholesterol increase: 0%, 2.6%, 1.3%, 4.6%, respectively
  • Triglyceride increase: 0%, 2.6%, 1.3%, 3.9%, respectively
  • Low-density lipoprotein (LDL) increase: 0%, 1.8%, 0.4%, 2.6%, respectively
  • Insulin increase: 0%, 0.9%, 1.7%, 4.6%, respectively

Change in Mean Weight and BMI Category (TR baseline to DB endpoint, median duration 156 days)

• Normal-weight (2.4 kg; P<0.001) and overweight (1.68 kg; P=0.008) groups significantly gained weight from TR baseline to DB endpoint.
• Weight increase ≥7% was observed in 5% and 8% of patients in the normal-weight and obese groups, respectively.
• Percentage of patients shifting towards a higher BMI category: underweight (60% [3/5]); normal-weight (18% [13/71]); overweight (9% [6/70])
• Percentage of patients shifting towards a lower BMI category: overweight (7% [5/70]); obese (9% [5/54])

Change in Mean Weight and BMI Category (TR baseline to OLE endpoint, median duration 204 days)

• With the exception of the obese group, significant increases in mean weight were observed for the underweight (3.82 kg; P=0.045), normal-weight (3.48 kg; P<0.001) and overweight (1.62 kg; P=0.003) groups.
• Weight increase ≥7% was observed in 15%, 6% and 4% of patients in the normal-weight, obese and overweight groups, respectively.
• Percentage of patients shifting towards a higher BMI category: underweight (67% [6/9]); normal-weight (28% [25/89]); overweight (16% [11/70])
• Percentage of patients shifting towards a lower BMI category: overweight (9% [8/84]); obese (19% [8/43])

Retrospective Study

Schoretsanitis et al (2022)⁷ retrospectively evaluated the effects of BMI, body weight, sex, age, and smoking status on the PK parameters of INVEGA SUSTENNA, including plasma concentrations and C/D.

Study Design/Methods

• A database of 439 paliperidone plasma concentrations from patients receiving INVEGA SUSTENNA was evaluated.

Results

Patient Characteristics

• Overall, 183 patients (obese [BMI ≥30 kg/m²], n=54; overweight [BMI
  ≥25 to <30 kg/m²], n=82; normal [BMI ≥18.5 to <25 kg/m²], n=47) were included. No patient was underweight (BMI <18.5 kg/m²). The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.

Pharmacokinetics

• No intergroup differences were reported in PK parameters across the BMI groups. See Table: Dosage and Plasma Concentrations of Paliperidone Across the BMI Groups.

• No significant difference in paliperidone plasma concentrations was observed in the post hoc pairwise comparison.
• No correlation between BMI or body weight and paliperidone plasma concentration or C/D values was reported.

CASE REPORT

Helland et al (2015)¹² described a case of subtherapeutic paliperidone concentrations (17-24 ng/mL) and prolonged elimination (t_½=142 days) following INVEGA SUSTENNA gluteal injections (two initiation doses plus four 234 mg monthly doses) in an obese patient (BMI 36.1 kg/m²) reported to have excessive subcutaneous fat. The authors hypothesized that erroneous injection into the subcutaneous fat may have resulted in delayed release of paliperidone, resulting in lower than expected blood levels during treatment and prolonged elimination upon discontinuation.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 28 March 2024.