Summary

• Due to its extremely low water solubility, paliperidone palmitate 6-month (PP6M) dissolves slowly after intramuscular (IM) injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and is predicted to last longer than 18 months.¹
• The pharmacokinetics (PK) of PP6M presented below are based on gluteal administration only.
• Following a single gluteal IM dose of PP6M at doses of 1,092 and 1,560 mg, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations (C_max) predicted on day 33 and 35, respectively. The release profile and dosing regimen of PP6M results in sustained therapeutic concentrations over 6 months.¹
• The median apparent half-life (t_1/2) of paliperidone following a dose of PP6M at 1,092 or 1,560 mg ranged from 148-159 days, respectively. After dosing of 1,560 mg PP6M is stopped, approximately 18% of the average steady-state levels remain in circulation after 18 months.¹
• PK simulations suggest that INVEGA HAFYERA doses of 1,092 mg (700 mg equivalent [eq.]) and 1,560 mg (1,000 mg eq.) result in a range of paliperidone exposures that are comparable to those obtained with corresponding doses of paliperidone palmitate 1-month (PP1M or INVEGA SUSTENNA) 156 mg (100 mg eq.) and 234 mg (150 mg eq.), respectively; corresponding doses of paliperidone palmitate 3-month (PP3M or INVEGA TRINZA) 546 mg (350 mg eq.) and 819 mg (525 mg eq.), respectively; or corresponding paliperidone extended-release (ER) tablets.²
• A population pharmacokinetic (popPK) model-based simulation of paliperidone PK after administration of INVEGA HAFYERA in patient subgroups based on age, sex, bodyweight, and renal function using data from a phase 3, double-blind (DB), noninferiority study revealed the following²:
  • The median paliperidone PK was not impacted by age and sex after attaining a steady state with PP6M.
  • Exposure to paliperidone was similar between INVEGA HAFYERA 1,560 mg (1,000 mg eq.) in patients with a normal renal function and INVEGA HAFYERA 1,092 mg (700 mg eq.) in patients with mild renal impairment (RI; creatinine clearance [CrCl] of 50-80 mL/min).
  • Following exposure to INVEGA HAFYERA 1,560 mg (1,000 mg eq.) or 1,092 mg (700 mg eq.), the median C_max decreased by 7.0% for overweight patients and 15.9% for obese patients as compared with that for patients with a normal weight.

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate 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.
• 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 and 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq. of paliperidone, respectively.

PUBLISHED and UNPUBLISHED DATA

PK Data for Paliperidone Palmitate 6-Month (PP6M)

Najarian et al (2021)³ conducted a phase 3, randomized, DB, active-controlled, parallel-group, multicenter, non-inferiority trial to evaluate the efficacy of INVEGA HAFYERA relative to INVEGA TRINZA (PP3M) 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 (PP1M) or INVEGA TRINZA.³

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

• Mean C_max was achieved around 1 month after each dose for all treatments and administered dosages.³
• Compared with patients who received INVEGA TRINZA, patients who received INVEGA HAFYERA had approximately 20%-25% lower paliperidone trough concentrations (dose normalized C_trough).³
• 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.³
• 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 PP6M C_trough is likely not the key determinant of relapse.³ 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 Double-Blind Phase.

There was consistent variability in exposure metrics (expressed as the % coefficient of variation [CV]) for PP3M and PP6M, ranging from 39% to 44% for AUC_{6 months}, 40% to 50% for C_max, and 39% to 65% for C_trough. These benchmarks were dose proportional among dosing schedules, whereas the dose-normalized AUC_6months was comparable across the dose range from 350 to 1000 mg eq.²

PK simulations suggest that PP6M doses of 1,092 mg (700 mg eq.) and 1,560 mg (1,000 mg eq.) result in a range of paliperidone exposures that are comparable to those obtained with corresponding doses of PP1M 156 mg (100 mg eq.) and 234 mg (150 mg eq.) or corresponding doses of PP3M 546 mg (350 mg eq.) and 819 mg (525 mg eq.), respectively, or to corresponding paliperidone ER tablets.² See Figure: Simulated Paliperidone Plasma Concentrations vs Time for the 1,092 mg (700 mg eq.) and 1,560 mg (1,000 mg eq.) Doses Compared to 156 mg (100 mg eq.) and 234 mg (150 mg eq.) Doses and Simulated Paliperidone Plasma Concentration Versus Time for 1,092 mg (700 mg eq.) and 1,560 mg (1,000 mg eq.) PP6M Compared to Every 3 Month Dosing for 546 mg (350 mg eq.) and 819 mg (525 mg eq.) of PP3M.

Special Population

• The popPK model utilized structural covariates CrCl, body mass index (BMI), and sex to evaluate the influence on paliperidone PK after INVEGA HAFYERA administration in patient subgroups based on age, sex, bodyweight, and renal function.²
• The PK dataset comprised 15,932 samples from 700 patients from the DB study (male, 68.4%; median [range] age, 40.0 [18-69] years; median [range] BMI, 27.2 [17.2-39.8] kg/m²:²
  • INVEGA TRINZA, 5,148 [32%] samples from 223 patients
  • INVEGA HAFYERA, 10,784 [68%] samples from 477 patients

Impact of Age and Sex

The median paliperidone PK was not impacted by age and sex after attaining a steady state with PP6M.²

Overweight or Obese Patients

• For the definition of the BMI covariate used in the analysis, see Table: Covariate - Body Mass Index.

• After a dose of INVEGA HAFYERA (1,560 mg [1,000 mg eq.] or 1,092 mg [700 mg eq.]), the median C_max decreased for overweight (-7.0%) and obese (-15.9%) patients as compared with that for patients with a normal body weight; the median C_trough was similar across all BMI subgroups.²

Patients with RI

Dose reduction of INVEGA HAFYERA for patients with mild RI was estimated by comparing dosing with INVEGA HAFYERA 1,560 mg (1,000 mg eq.) in patients with a normal renal function with dosing with INVEGA HAFYERA 1,092 mg (700 mg eq.) in patients with mild RI.² For the definition of the CrCl covariate used in the analysis, see Table: Covariate - CrCl.

• Compared with in patients with a normal renal function, the median values of the C_max and C_trough of paliperidone increased by 19.1% and 19.5%, respectively, in patients with mild RI (50-80 mL/min) when both groups were receiving maintenance doses of INVEGA HAFYERA 1,560 mg (1,000 mg eq.).
• Compared with in patients with a normal renal function who received INVEGA HAFYERA 1,560 mg (1,000 mg eq.), the median C_max and C_trough of paliperidone decreased by 15.4% and 17.7%, respectively, in patients with mild RI after receiving a reduced dose of INVEGA HAFYERA 1,092 mg (700 mg eq.).
• Irrespective of the CrCl cutoff values used, the paliperidone exposure in patients with mild RI who received INVEGA HAFYERA 1,092 mg (700 mg eq.) was similar to that in patients with a normal renal function who received INVEGA HAFYERA 1,560 mg (1,000 mg eq.).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug Files (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 05 December 2024.