Summary

• Due to its extremely low water solubility, INVEGA SUSTENNA (paliperidone palmitate 1-month [PP1M]) dissolves slowly after intramuscular (IM) injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation.¹
• After a single IM injection of PP1M, plasma concentrations of paliperidone gradually rise to reach observed maximum plasma concentration (C_max) at a median time to reach the maximum plasma concentration (t_max) of 13 days.¹ Release of paliperidone starts as early as one day after the injection and lasts for as long as 126 days.¹ The median plasma elimination half-life (t_½) of paliperidone following PP1M administration over the dose range of 39-234 mg is 25-49 days.²
• A 28% higher C_max was observed following IM injection of single doses (39-234 mg) of PP1M in the deltoid muscle as compared with the gluteal muscle.²
• Interruption or discontinuation of treatment with PP1M results in a slow decline in plasma concentrations.³ Results from a population pharmacokinetic (PK) simulation model suggested that re-initiation of PP1M after missed maintenance doses requires the use of specific strategies dependent on the time since the last injection.⁴
• Simulation results from a population PK model⁵ suggested that patients who received the recommended dosing regimen for the treatment of schizophrenia (234 mg in the deltoid muscle on day 1 and 156 mg on day 8, and 117 mg every four weeks thereafter) had steady-state exposure profiles that were similar to those seen for patients who received paliperidone ER 6 mg tablets daily.^6,7 The two initial deltoid IM injections of 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly, with no oral supplementation required.²
• Results from an open-label, randomized study in Chinese patients with schizophrenia showed that the PK parameters of PP1M (39-234 mg) were linear with respect to time.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 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.

• PP1M doses expressed as 25, 50, 75, 100, and 150 mg eq. are equal to 39, 78, 117, 156, and 234 mg of paliperidone palmitate, respectively.

PUBLISHED AND UNPUBLISHED DATA

General Pharmacokinetics

Coppola et al (2012)⁹ conducted an open-label, multiple-dose, multicenter one-year study in clinically stable patients with DSM-IV diagnosis of schizophrenia to assess the PK parameters of the 234 mg dose of PP1M.

The study consisted of a washout phase (up to 21 days) and a 53-week open-label treatment phase during which patients received the first injection of 234 mg of PP1M in the deltoid muscle on day 1 followed by a second injection on day 8 in the deltoid. PP1M plasma concentrations were obtained at all visits.

Of the 212 patients (mean age: 40.7 years; 73% male) 186 patients received 234 mg throughout the study. Patients achieved steady-state plasma concentration levels after eight to nine months. The C_max levels were similar after the second and eighth injections and slightly higher after the 14th injection, while the median fluctuation index decreased over the injection period. Details of these and other PK parameters are presented in Table: Median PK Parameters of Paliperidone Palmitate 234 mg Assessed after the Second, Eighth, and 14th Intramuscular Injection.

Deltoid vs. Gluteal Administration

Cleton et al (2014)¹⁰ conducted an international, multicenter, single-dose, open-label, randomized, parallel-group PK study in clinically stable adult patients with DSM-IV diagnosis of schizophrenia to assess the dose proportionality of PP1M following a single IM injection into the deltoid or gluteal muscle.

The study consisted of a 21-day screening phase and an open-label treatment period with up to 126 days of follow-up. Each patient (N=201) received a single dose of PP1M (39, 78, 156, or 234 mg) administered as an IM injection into either the deltoid or gluteal muscle. Patients without prior exposure to risperidone, risperidone long-acting injection (RLAI), paliperidone or PP1M underwent oral tolerability testing (paliperidone ER 3 mg/day for 4 doses) at least 8 days before the first PP1M injection to allow time for washout.

Total exposure to paliperidone (median AUC_∞, dose-normalized to 78 mg) increased proportionally after single-dose IM injections of PP1M 39-234 mg at both injection sites. A slightly less than dose-proportional outcome was found for C_max at both injection sites, and the mean C_max was lower for PP1M 156 mg injected in the deltoid muscle and 156 mg and 234 mg injected in the gluteal muscle. Median C_max was generally higher for the PP1M deltoid injections than for the gluteal injections. Median t_max ranged from 13-17 days across all doses and both injection sites. The plasma concentration-time curves (median dose normalized to 78 mg) and total exposure to paliperidone (median dose-normalized AUC_∞) were similar between all doses of PP1M and both injection sites. For both the deltoid and gluteal injection sites, median t_½ increased as the dose increased.

Rossenu et al (2014)¹¹ conducted a randomized, single-center, open-label, parallel-group, PK study in clinically stable adult patients with DSM-IV diagnosis of schizophrenia (n=49) to evaluate the PK parameters of PP1M at steady state following multiple IM injections into the deltoid and gluteal muscles.

The study consisted of a 21-day screening phase and a 176-day treatment period during which patients received 4 injections of PP1M 156 mg administered into either the deltoid (n=24) or gluteal (n=25) muscles on days 1, 8, 36, and 64. Patients without prior exposure to risperidone, RLAI, paliperidone or PP1M underwent oral tolerability testing (paliperidone ER 3 mg/day for 4 doses) at least 8 days before the first PP1M injection to allow time for washout.

The mean plasma concentration-time profile of PP1M 156 mg administered in the deltoid muscle was consistently higher than that of PP1M 156 mg administered in the gluteal muscle.

AUC_T (AUC within the interval of 28 days after the 2^nd and 4^th IM injections), C_max, and FI (fluctuation index, after 4^th injection) were higher in patients who received deltoid injections of PP1M 156 mg than in those who received gluteal injections.

Mean pre-dose plasma concentrations on days 8, 36, and 64, and postdose on day 92 slightly increased after day 8 which suggested that patients were not completely at steady state 7 days after the first injection. The increase was more evident for the patients receiving gluteal injections than for those receiving deltoid injections. The C_max and AUC_T for PP1M were 30% and 20% higher for deltoid versus gluteal muscle injections, respectively. Details of these PK parameters are presented in Table: Median PK Parameters of Paliperidone Palmitate 156 mg Assessed after the Second and Fourth Intramuscular Injections.

Dosing Window Flexibility

Samtani et al (2009)⁴ reported results on dosing-window flexibility during initiation or maintenance treatment and management of missed doses of PP1M from a population PK simulation model. The PK simulation model assessed PK exposure of PP1M in patients with variations in dosing during the initiation phase (injection on day 8 ±2 days), the maintenance phase (day 36 and monthly injections ±7 days), and during steady-state (missed dose from one month to less than six weeks; six weeks to less than six months; and more than six months after the previous dose). Visual inspection of simulated curves was used to determine the time point at which re-initiation with two doses would be appropriate.

Dosing-Window Flexibility during Treatment Initiation: Comparison between simulations for patients who received their second initiation dose (PP1M 156 mg) within two days of the recommended injection on day 8 showed that the median C_max varied by ±2 ng/mL.

Dosing-Window Flexibility during Maintenance Treatment: PK simulations used the PP1M 234 mg dose to establish dosing flexibility during maintenance dosing. The median C_max decreased by 8% (from 52-48 ng/mL) at +7 days and increased by 4% (from 52-54 ng/mL) at -7 days of the scheduled monthly maintenance injection. Although a dosing window of ±7 days is acceptable during monthly dosing of PP1M after day 36, it should be considered the exception and does not imply that the dosing interval can be changed to three- or five-week cycles.

Management of Missed Doses during Steady-State Treatment: PK modeling simulations suggest that the strategy for re-initiation of PP1M treatment after missed doses during maintenance treatment should depend on the amount of time that has elapsed since the last injection. Please refer to the PP1M approved labeling for complete information.

Samtani et al (2013)¹² described the results of additional PK simulations evaluating the effect of expanding the window to ± 4 days on either side of the recommended day 8 injection.

When comparing regimens in which administration of the second initiation dose (PP1M 156 mg) occurred on either day 4, day 8, or day 12, there was a ± 3 ng/mL variation in median maximum plasma concentrations, with considerable overlap. The day 1/day 4 regimen resulted in minor concentration excursions that exceeded the exposure window for the day 1/day 8 regimen by approximately 1 day around the C_max.

Interruption of Therapy/Discontinuation

Samtani et al (2012)³ conducted a PK simulation to evaluate antipsychotic plasma concentrations after discontinuation or interruption of therapy with oral and long-acting injectable formulations of risperidone and paliperidone. The results for PP1M are presented below.

The simulation assumed individuals were at steady-state and then entered into one of three separate discontinuation/interruption scenarios, with medication-specific re-initiation strategies used in the interruption scenarios: Scenario 1) Complete discontinuation; Scenario 2) One week of treatment interruption followed by administration of PP1M 117 mg every 4 weeks; or Scenario 3) Four weeks of treatment interruption followed by administration of PP1M 117 on days 28 and 35 (weeks 4 and 5) and every 4 weeks thereafter.

PK modeling was used to predict plasma concentrations over an 8- to 9-week period following treatment discontinuation or interruption, and to determine the lowest concentrations during the modeled period as a percentage of the steady-state C_min in the two interruption scenarios.

Scenario 1: Discontinuation of PP1M led to a slow, steady decrease in plasma concentrations to 7.2 ng/mL at week 8.

Scenario 2: A 1-week treatment interruption of PP1M led to a decrease in plasma concentrations to 90% of steady-state C_min.

Scenario 3: A 4-week treatment interruption of PP1M led to a decrease in plasma concentrations to 64% of steady-state C_min. Upon re-initiation, there was a rapid reattainment of plasma concentrations.

Body Weight

Helland et al (2015)¹³ described a case of subtherapeutic paliperidone concentrations (17-24 ng/mL) and prolonged elimination (t_½=142 days) following PP1M 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.

Ethnicity

Si et al (2014)⁸ conducted an open-label, randomized, parallel group, multicenter study in clinically stable schizophrenia patients to assess the PK parameters of PP1M 39, 156 and 234 mg in Chinese patients with schizophrenia.

Two phase study design: 1) Screening phase (up to 21 days): For patients with undocumented tolerability to oral risperidone or paliperidone or RLAI, paliperidone ER 3 mg/day for 2 consecutive days was administered at least 5 days prior to randomization; 2) Open-label treatment phase (up to 210 days): Eligible patients were randomized (1:1:1) to 39, 156 or 234 mg on day 1 via gluteal injection. On day 8, the same dose was received via the alternate gluteal muscle and continued at a fixed dose monthly for 210 days following the first PP1M injection.

The study was completed by 93.8% (15/16), 93.8% (15/16) and 81.3% (13/15) of patients in the 39, 156 and 234 mg PP1M treatment groups, respectively.

PK parameters following doses on days 1 and 8 are provided in the Table: PK Parameters for Paliperidone Palmitate 39, 156 and 234 mg Following Gluteal Administration on Days 1 and 8. The time to maximum concentration (t_max), elimination half-life (t_1/2) and apparent oral clearance (CL/F) were comparable across all three treatment doses. Significant and dose-proportional differences in the maximum plasma concentration (C_max) and area under the plasma concentration time curve to day 35 (AUC _{[0–35 days]}), day 210 (AUC _{[0–210 days]}) and infinity (AUC _[0–∞], extrapolated) were observed.

OTHER RELEVANT LITERATURE

Result of an analysis by Patteet et al (2016)¹⁴ revealed that steady-state concentrations of paliperidone were not influenced by CYP2D6 polymorphisms. When a distinction was made between patients receiving oral vs long-acting paliperidone therapy, the concentration-to-dose ratio (C/D) was higher for paliperidone administered as a long-acting injection versus orally (mean C/D: 8.81 ng/mL/mg vs 4.63 ng/mL/mg, respectively). Reddy et al (2013)¹⁵ used PP1M data as an external validation for a PK-pharmacodynamic model to describe the treatment effect of several antipsychotic drugs. Sheehan et al (2012)¹⁶ compared peak-to-trough fluctuations in plasma concentrations between long-acting injectable antipsychotics, including PP1M, and their oral equivalents. A review article by Samtani et al (2011)¹⁷ described dosing and switching strategies for PP1M, based on the results of population PK modeling. Samtani et al (2009)¹⁸ presented the results of population PK modeling and simulations evaluating the PK profile of PP1M in special populations including renal impairment, elderly patients, and differing body mass index. Samtani et al (2009)^5-7 evaluated the optimal initiation and maintenance dosing strategies for PP1M in adults with schizophrenia in a population PK simulation.

Yin et al (2015)¹⁹ proposed that the deltoid and gluteal intramuscular administration sites are not interchangeable for maintenance dosing with PP1M. The authors relied on conclusions from a single-dose pharmacokinetic study¹⁰ with PP1M (with a limited sample size) and extrapolated to multiple dose and maintenance treatment with PP1M.

• Janssen developed a robust population pharmacokinetic model using both single and multiple dose pharmacokinetic data.⁵ The PK model utilized data from 1795 subjects from six phase 1 trials and five phase 2 and 3 trials with a total of 18,530 PK samples from many different countries and ethnicities.
• As reflected in the product labeling, the interchangeability between deltoid and gluteal intramuscular injections for maintenance dosing was supported by the submission of the relevant pharmacokinetic and clinical data for PP1M.
• In addition, in a 25-week randomized, crossover study by Hough et al (2009)²⁰, there was little difference in plasma paliperidone concentrations between the deltoid and gluteal sites for a given dose when at apparent steady state.
• It is true that there may be difficulty in reaching the musculature in the gluteal injection site due to the thickness of the adipose tissue (likely from BMI>30), and this is a primary reason that the two initiation doses of PP1M are required to be administered in the deltoid muscle in addition to the requirement for weight-based selection of the appropriate needle size for administration.

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 21 December 2023