Summary

• Due to its extremely low water solubility, INVEGA TRINZA dissolves slowly after intramuscular (IM) injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation.¹
• Following a single IM dose of INVEGA TRINZA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations (C_max) at a median time (t_max) of 30-33 days. The release of drug starts as early as day 1 and lasts for as long as 18 months.²
• Following IM injection of INVEGA TRINZA at doses of 273-819 mg in the deltoid muscle, on average, an 11%-12% higher C_max was observed compared with injection in the gluteal muscle.²
• The median apparent half-life (t_1/2) of paliperidone following INVEGA TRINZA administration over the dose range of 273-819 mg ranged from 84-95 days following deltoid injections and 118-139 days following gluteal injections.³
• Results from a phase 3, double-blind (DB), randomized study in patients with schizophrenia revealed that the dose-normalized C_max was approximately 1.4- to 1.5-fold higher in patients receiving INVEGA HAFYERA compared with patients receiving INVEGA TRINZA and the dose-normalized trough plasma concentration (C_trough) was approximately 20%-25% lower in patients receiving INVEGA HAFYERA compared with patients receiving INVEGA TRINZA. The dose-normalized total drug exposure in 6 months (AUC_6month) was comparable in patients receiving INVEGA HAFYERA and INVEGA TRINZA.⁴
• Results from a phase 1, open-label, randomized study in patients with schizophrenia and schizoaffective disorder showed that the pharmacokinetics (PK) of paliperidone palmitate were dose-proportional across a dose range of 273-819 mg.⁵
• Results from a prospective, observational study in patients with schizophrenia showed that the plasma levels of INVEGA TRINZA ranged from 19.09-35.01 ng/mL. The mean (standard deviation [SD]) paliperidone plasma levels after 28 days of the first INVEGA TRINZA injection was 23.56 (11.98) ng/mL.⁶
• Results from a prospective, observational study in patients with severe schizophrenia (Clinical Global Impression-Severity [CGI-S]≥5) reported plasma levels (PLs) above the therapeutic range in 12 out of 22 patients treated with standard doses of INVEGA TRINZA.^7,8

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release 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 milligrams 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.
• INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq of paliperidone, respectively.
• INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq of paliperidone, respectively.

PUBLISHED AND UNPUBLISHED DATA

Najarian et al (2022)⁴ conducted a phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority trial to evaluate the efficacy of INVEGA HAFYERA relative to INVEGA TRINZA on time to first relapse and to assess the safety and PK in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA.

Study Design/Methods

The study consisted of the following phases:

• Screening phase (≤28 days)
• Open-label transition phase (1-4 months; 1-5 injections of INVEGA SUSTENNA)
• Open-label maintenance phase (1 or 3 months; 1 injection of INVEGA SUSTENNA or INVEGA TRINZA)
• DB phase (12 months; 4 injections of INVEGA TRINZA or 2 injections of INVEGA HAFYERA and 2 placebo injections)

Results

Patient Characteristics

Overall, 702 of the 838 included patients completed the open-label phases and were randomized to the DB phase (INVEGA HAFYERA, n=478; INVEGA TRINZA, n=224). In the DB phase, the mean (SD) duration of exposure was 336.4 (80.89) days in the INVEGA TRINZA group and the mean (SD) dose of INVEGA TRINZA was 442.2 (87.57) mg eq. A total of 84.8% of patients in the INVEGA TRINZA group received 4 active injections.

Pharmacokinetics

In the DB phase, clinically stable patients received 1,092 and 1,560 mg INVEGA HAFYERA or 546 and 819 mg INVEGA TRINZA:

• The mean C_max was achieved around 1 month after each dose for all treatments and administered dosages. After achieving C_max, plasma concentrations gradually declined for the rest of the dosing cycle.
• Compared with patients who received INVEGA TRINZA, patients who received INVEGA HAFYERA had approximately 20%-25% lower paliperidone trough concentrations (dose-normalized C_trough values).
• Mean peak paliperidone concentrations (dose-normalized C_max) after INVEGA HAFYERA dosing compared to after INVEGA TRINZA dosing was slightly higher (1.4- to 1.5-fold) and mean total paliperidone exposure (dose-normalized AUC_6month) after INVEGA TRINZA and INVEGA HAFYERA dosing was comparable.
• Both the median and the mean peak to trough ratios were approximately 2-fold higher in patients receiving INVEGA HAFYERA compared with patients receiving INVEGA TRINZA.⁴
• Relapses did not appear to be clustered near the end of dosing cycle and were observed throughout dosing cycle for both treatments, suggesting that the comparably lower INVEGA HAFYERA C_trough is likely not the key determinant of relapse. See Figure: Semi-logarithmic mean (SD) Plasma-Concentration Time Profiles of Paliperidone After Administration of INVEGA TRINZA at 546 or 819 mg and INVEGA HAFYERA at 1,092 or 1,560 mg (PK Data Analysis Set) in the DB Phase.

Dosing PK Data for Paliperidone Palmitate

Ravenstijn et al (2016)⁵ conducted a study to evaluate the PK, safety, and tolerability of a single INVEGA TRINZA dose (468 mg gluteal IM injection) and single escalating doses of INVEGA TRINZA (117-819 mg deltoid/gluteal IM injection) in patients with schizophrenia or schizoaffective disorder.

Study Design/Methods

The study was a phase 1, randomized, open-label, multicenter, parallel-group study in clinically stable (defined as Positive and Negative Syndrome Scale total score of ≤70) patients (aged 18-65 years; body mass index [BMI] of 17-35 kg/m² and body weight ≥47 kg) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder. Patients were allocated to 1 of 4 separately conducted panels (A to D) that each consisted of a screening period (≤21 days) and an open-label period with 2 single-dose treatment periods. The periods were separated by a 7-21-day washout interval.

• Period 1: Paliperidone immediate-release (IR) 1 mg (IM, deltoid/gluteal)
• Period 2:
  • Panel A: INVEGA TRINZA 468 mg (gluteal)
  • Panel B: INVEGA TRINZA 117, 234, or 702 mg (gluteal) or 468 or 702 mg (deltoid)
  • Panel C: INVEGA TRINZA 234 mg (gluteal)
  • Panel D: INVEGA TRINZA 273 mg (deltoid), 546 mg (gluteal), 819 mg (gluteal), or 819 mg (deltoid)
• Please note that the dosage strengths utilized in panels A, B, and C are not commercially available dosage strengths of INVEGA TRINZA.

The patients were allowed to continue their existing antipsychotic medications so long as they did not interfere with the PK of paliperidone. The following agents were prohibited: oral risperidone, paliperidone, clozapine, ziprasidone, thioridazine, and all long-acting injectable antipsychotics. Hepatic enzyme inducers, certain anticonvulsants, and drugs that prolong the QT interval were also prohibited. Plasma samples were collected predose and up to 96 hours postdose during period 1 and predose and up to 364 days postdose during period 2. Additional samples were taken on days 454 and 544 for the extension period. The PK analysis set included patients who completed both period 1 and period 2.

Results

Patient Characteristics

A total of 328 patients were enrolled in 4 panels (panel A: 74, panel B: 129, panel C: 25, panel D: 100). Of these patients, 325 received paliperidone IR 1 mg and 308 received INVEGA TRINZA (117-819 mg). A total of 245 patients completed the study (panel A: 48, panel B: 104, panel C: 22, panel D: 71). The mean age range of patients was 41.4-42.6 years, 66.5% were men, and 56.6% were White.

PK Parameters

Only panel B and D data were used for PK analysis, as the results of panels A and C were compromised by incomplete injections of INVEGA TRINZA in certain patients as a result of inadequate shaking before injection (estimated relative bioavailability in panels A and C ranged from 59%-90%).

• t_max ranged from 24-34 days (deltoid) and 23-31 days (gluteal). t_1/2 was approximately 2-4 months after a single IM (deltoid/gluteal) injection of INVEGA TRINZA 117-819 mg.
• Median plasma area under the plasma concentration-time curve from time 0 to infinite time (AUC_∞) and C_max of paliperidone increased in a dose-dependent manner.
• Across all doses, a higher least square mean C_max (~27%) was observed following INVEGA TRINZA deltoid administration compared with gluteal administration. A similar AUC_∞ of paliperidone was observed between both injection sites.

Details of these PK parameters are presented in Table: PK Parameters of Paliperidone Following Deltoid Administration of INVEGA TRINZA (Panels B and D, Period 2), PK Analysis Set and Table: PK Parameters of Paliperidone Following Gluteal Administration of INVEGA TRINZA (Panels B and D, Period 2), PK Analysis Set.

• The relative bioavailability of INVEGA TRINZA in comparison with paliperidone IR was approximately 100%, independent of the dose, injection site, BMI, sex, or ethnicity.

Safety and Tolerability

A total of 26.8% (87/325) of patients during period 1 and 73.7% (227/308) of patients during period 2 experienced ≥1 treatment-emergent adverse event (TEAE). TEAEs should be interpreted with caution because patients were taking concomitant antipsychotics, which could be changed during the study. Across all panels, the most common (>7%) TEAEs during period 2 were headache and nasopharyngitis, and the majority of TEAEs were mild to moderate in severity. Serious TEAEs occurred in 35 patients and were mostly psychiatric in nature. There was 1 death due to metastatic melanoma (panel B), which was not considered to be associated with the study drug. Twenty-five patients (18 deltoid, 7 gluteal) reported injection site-related TEAEs during period 2, and 1 patient reported severe pain. Mean visual analogue scale scores were low across all panels for evaluation of injection-site pain and decreased within 2-4 days.⁵

PK Data After Switching From INVEGA SUSTENNA to INVEGA TRINZA

Mauri et al (2022)⁶ conducted a prospective, observational study to evaluate the maintenance of clinical efficacy and tolerability, and variation of paliperidone plasma levels during transition from INVEGA SUSTENNA to INVEGA TRINZA.

Study Design/Methods

• Patients aged 18-66 years with schizophrenia were included, and observation was ongoing at the time of reporting.
• Clinical assessments were performed at the time of the first INVEGA SUSTENNA administration and then every 28 days up to the time of switching to INVEGA TRINZA, followed by 28 days and 2 months after the first INVEGA TRINZA administration and then every 3 months until 9 months of the first INVEGA TRINZA administration.
• All patients were stabilized on INVEGA SUSTENNA for 4 months, following which patients were switched to INVEGA TRINZA.

Results

Overall, 22 patients were included (mean age, 46.91 years) in the study. The plasma levels ranged from 16.40-30.22 ng/mL for INVEGA SUSTENNA, and 19.09-35.01 ng/mL for INVEGA TRINZA. See Table: Paliperidone Plasma Levels During and After Transitioning to INVEGA TRINZA.

After a slight initial increase, plasma levels were stabilized after the fourth administration of INVEGA SUSTENNA, and a slight reduction in plasma levels (not statistically significant) was observed during treatment with INVEGA TRINZA.

• After steady-state paliperidone concentrations were achieved with INVEGA SUSTENNA, the stability of plasma concentration of paliperidone was maintained during the transition to INVEGA TRINZA without oral supplementation of paliperidone.

Dose and Plasma Levels in an Observational Study of INVEGA TRINZA

Fernández-Miranda et al (2023 and 2024)^7,8 conducted a prospective, observational study to evaluate the relationships between dose, PL, and clinical outcomes to different doses of INVEGA TRINZA and 1-month aripiprazole for the treatment of patients with severe schizophrenia.

Study Design/Methods

• A total of 68 adult patients with severe schizophrenia (CGI-S≥5) and receiving stabilized doses of INVEGA TRINZA or 1-month aripiprazole for at least a year were included in the study.^7,8
• Patients were categorized into 2 dose-based groups: standard dose (n=22; INVEGA TRINZA, ≤819 mg/3 months) and high dose (n=21; INVEGA TRINZA >819 mg/3 months).^7,8
• PLs were categorized into 2 ranges: recommended therapeutic range or standard range (INVEGA TRINZA 20-60 ng/mL) and high range (above standard range).^7,8
• The study evaluated the dose-PL relationship with treatment adherence, effectiveness, safety, and tolerability as well as blood biochemistry.^7,8

Results

• The patient population was 76.5% male, with a mean age of 48.1 years, and a baseline CGI-S score of 5.4.^7,8
• For doses and PLs of INVEGA TRINZA see Table: Doses and Plasma Levels of INVEGA TRINZA.

• The dose-PL relationship was not completely linear.^7,8
  • Standard dose group: 54.5% (12/22) of patients achieved higher PLs (P<0.001), and 45.5% (10/22) achieved standard PLs.
  • High dose group: 90.5% (19/21) of patients achieved higher PLs, and 9.5% (2/21) achieved standard PLs.
• The relative risk (RR) for high PLs was nearly double in the high dose group compared to the standard dose group: INVEGA TRINZA RR, 2.2; 1-month aripiprazole RR, 2.3.⁸
• All patients continued treatment regardless of antipsychotic type, dose, or PL; no treatment withdrawal was reported for higher doses.^7,8
• Disease severity decreased (measured by CGI-S score at 1 year) more frequently for patients with greater severity at baseline; however, these patients were also treated with higher doses.^7,8
• Hospital admissions primarily decreased in patients with high PLs.^7,8
• None of the reported adverse effects were serious or led to a change in treatment.^7,8
• Adverse effects were generally not proportional to PLs, except parkinsonism with high doses of INVEGA TRINZA.^7,8
• The most common changes in blood biochemistry were elevations in lipids and prolactin levels, and elevations in prolactin were significantly related to high PLs of INVEGA TRINZA (P<0.05).^7,8

Population PK

A population PK analysis was performed to characterize the dose-concentration relationship of INVEGA TRINZA.⁹ Plasma concentrations of paliperidone were obtained from a single-dose, phase 1 study and a repeated-dose, phase 3 study.^5,10 The final population PK model is a 1-compartment disposition model with first-order elimination and was based on 8,990 paliperidone PK samples from 651 subjects. The following parameters were identified as covariates on K_a1max of the slow absorption process: creatinine clearance on clearance, BMI on volume of distribution, injection volume on absorption rates, injection site and sex. The final model provided a good description of the PK characteristics of INVEGA TRINZA when administered as single and multiple injections.

Additionally, Magnusson et al¹¹ conducted a review of the pharmacokinetic rationale of dosing and switching strategies for INVEGA TRINZA. Pharmacokinetic modeling and simulation, as well as clinical trial data, were used to support: plasma exposures for switching from INVEGA SUSTENNA to INVEGA TRINZA, dosing of INVEGA TRINZA once every 3 months, dosing windows and managing missed doses of INVEGA TRINZA, dosing in special patient populations, and secondary pharmacokinetic parameters following deltoid or gluteal administration of INVEGA TRINZA.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 07 January 2025.