Invega Hafyera Mechanism of Action

Pharmacology: Mechanism of Action: Paliperidone palmitate is hydrolyzed to paliperidone [see Pharmacokinetics as follows]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, its efficacy in the treatment of schizophrenia could be mediated through a combination of central dopamine D₂ and serotonin 5HT_2A receptor antagonism.
Pharmacodynamics: In vitro, paliperidone acts as an antagonist at the central dopamine D₂ and serotonin 5HT_2A receptors with binding affinities (Ki values) of 1.6-2.8 nM and 0.8-1.2 nM, respectively. Paliperidone also acts as an antagonist at histamine H₁ and α₁ and α₂ adrenergic receptors with bindings affinities of 32, 4, and 17 nM, respectively. Paliperidone has no appreciable affinity for cholinergic muscarinic or β₁- and β₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar in vitro.
Clinical Studies: The efficacy of INVEGA HAFYERA for the treatment of schizophrenia in patients who had previously been stably treated with either PP1M for at least 4 months or PP3M for at least one 3-month injection cycle was evaluated in a randomized, double-blind, active-controlled, interventional, parallel-group, multicenter, non-inferiority study designed to evaluate time to relapse in adults with a DSM-5 diagnosis of schizophrenia.
Patients could enter the study if previously treated with PP1M at dosages of 100 or 150 mg, PP3M at dosages of 350 or 525 mg, injectable risperidone at dosages of 50 mg, or any oral antipsychotic with a reason to change (e.g., efficacy, safety, tolerability, or a preference for a long-acting injectable medication) and with a PANSS total score of <70 points.
After establishing tolerability with PP1M (at dosages of 100 or 150 mg) or PP3M (at dosages of 350 or 525 mg) and clinical stability, defined by having a PANSS total score of <70 points for the previous 2 assessments prior to the double-blind phase, patients were randomized in a 2:1 ratio to receive INVEGA HAFYERA (478 patients) or PP3M (224 patients).
The primary efficacy variable was time to first relapse in the double-blind phase. The primary efficacy analysis was based on the difference in Kaplan-Meier 12-month estimates of percentage of subjects remaining relapse-free between INVEGA HAFYERA and 3-month paliperidone palmitate prolonged-release suspension for injection. Relapse was pre-defined as emergence of one or more of the following: psychiatric hospitalization, ≥25% increase (if the baseline score was >40) or a 10-point increase (if the baseline score was ≤40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation: a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items.
A relapse event was experienced by 7.5% and 4.9% of patients in the INVEGA HAFYERA and PP3M treatment groups, respectively, with the Kaplan-Meier estimated difference (INVEGA HAFYERA - PP3M) of 2.9% (95% CI: -1.1 to 6.8). The upper bound of the 95% CI (6.8%) was less than 10%, the prespecified non-inferiority margin. The study demonstrated non-inferiority of INVEGA HAFYERA to PP3M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1. (See Figure 1.)

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An evaluation of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.
Pharmacokinetics: The pharmacokinetics for INVEGA HAFYERA presented as follows are based on gluteal administration only.
INVEGA HAFYERA delivers paliperidone over a 6-month period, compared to the 1-month or 3-month products which are administered every month or every three months, respectively. INVEGA HAFYERA doses of 700 mg and 1,000 mg result in paliperidone total exposure ranges that are encompassed within the exposure range for corresponding doses of 1-month paliperidone palmitate prolonged-release suspension for injections (PP1M) (100 mg and 150 mg of paliperidone) or corresponding doses of 3-month paliperidone palmitate (PP3M) prolonged-release suspension for injections (350 mg and 525 mg of paliperidone, respectively) or to corresponding once daily doses of paliperidone extended-release tablets. However, mean trough concentrations (C_trough) at the end of the dosing interval were approximately 20-25% lower for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate prolonged-release suspension for injections. The mean peak concentration (C_max) was higher (1.4 to 1.5-fold) for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate prolonged-release suspension for injections.
Inter-subject variability in paliperidone PK parameters for INVEGA HAFYERA ranged from 42 to 48% for AUC_6months and ranged from 56 to 103% for C_max. Because of the difference in pharmacokinetic profiles among the four paliperidone products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.
Absorption: Due to its extremely low water solubility, the 6-month formulation of paliperidone palmitate dissolves slowly after intramuscular 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.
Following gluteal injection(s) of INVEGA HAFYERA at doses of 700 or 1,000 mg plasma concentrations of paliperidone rise to reach maximum concentrations at a median T_max of 29 to 32 days. The release profile and dosing regimen of INVEGA HAFYERA results in sustained concentrations over 6 months. The total and peak dose-normalized exposures of paliperidone following INVEGA HAFYERA administration were comparable between 700 mg and 1,000 mg dose levels. The median steady-state peak:trough ratio for an INVEGA HAFYERA dose is 3.1 and 3.0 following gluteal administration of 700 and 1,000 mg, respectively.
Distribution: Following administration of INVEGA HAFYERA, the apparent volume of distribution of paliperidone is 1,960 L.
The plasma protein binding of racemic paliperidone is 74%.
Elimination: Metabolism: In a study with oral immediate-release ¹⁴C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release ¹⁴C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.
Excretion: The median apparent half-life of paliperidone following a single INVEGA HAFYERA of either 700 mg or 1,000 mg was 148 and 159 days, respectively. The concentration of paliperidone remaining in the circulation 18 months after dosing of 1,000 mg 6-month paliperidone (as palmitate) prolonged-release suspension for injection stopped is estimated to be 18% of the average steady-state levels.
Drug Interaction Studies: No specific drug interaction studies have been performed with INVEGA HAFYERA. The following information is obtained from studies with oral paliperidone.
Effects of other drugs on the exposures of INVEGA HAFYERA are summarized in Figure 2. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C_max and AUC values at steady-state was observed (see Figure 2). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration of paliperidone, a decrease in mean C_max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drugs Having Clinically Important Interactions with INVEGA HAFYERA under Interactions]. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. (See Figure 2.)

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In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drugs Having No Clinically Important Interactions with INVEGA HAFYERA under Interactions].
Co-administration of a single dose of an oral paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C_max and AUC of paliperidone. Since no significant effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium extended-release tablets and INVEGA HAFYERA. This interaction has not been studied with INVEGA HAFYERA.
In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.
The effects of INVEGA HAFYERA on the exposures of other drugs are summarized in Figure 3.
After oral administration of paliperidone, the steady-state C_max and AUC of valproate were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3-15 mg/day was added to their existing valproate treatment [see Drugs Having Clinically Important Interactions with INVEGA HAFYERA under Interactions]. (See Figure 3.)

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Specific Populations: No specific pharmacokinetic studies have been performed with INVEGA HAFYERA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA HAFYERA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 4 [see Renal Impairment under Precautions].
Patients with Hepatic Impairment: After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Hepatic Impairment under Precautions].
Geriatric Patients: After oral administration of paliperidone in elderly subjects, the C_max and AUC increased 1.2-fold compared to young subjects. This may be attributable to age-related decreases in creatinine clearance [see Use in the Elderly under Precautions]. (See Figure 4.)

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Smokers: Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.
Male and Female Patients: Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with 6-month paliperidone palmitate prolonged-release suspension for injection the trough concentrations were similar between males and females.
Obese Patients: Lower C_max was observed in overweight and obese subjects. At apparent steady state with INVEGA HAFYERA, the trough concentrations were similar among normal, overweight, and obese subjects.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No carcinogenicity studies were conducted with the 6-month paliperidone palmitate prolonged-release suspension for injection.
The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate prolonged-release suspension for injection was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which are ~0.7, 2 and 4 times, respectively, the MRHD of 234 mg of the 1-month paliperidone palmitate prolonged-release suspension based on mg/m² body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at ~2 and 4 times the MRHD of 234 mg of the 1-month paliperidone palmitate prolonged-release suspension based on mg/m² body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate.
Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone based on mg/m² body surface area (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D₂ antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Hyperprolactinemia under Precautions].
Mutagenesis: Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test.
Impairment of Fertility: No fertility studies were conducted with the 6-month paliperidone palmitate prolonged-release suspension for injection.
In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the oral MRHD of 12 mg based on mg/m² body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at an oral dose of 0.63 mg/kg, which is half of the oral MRHD of 12 mg based on mg/m² body surface area.
The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the oral MRHD of 12 mg/day based on mg/m² body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m² body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).
Animal Toxicology and/or Pharmacology: Injection site toxicity was assessed in minipigs injected intramuscularly with the 6-month paliperidone palmitate prolonged-release suspension for injection at doses up to 2,115 mg, which is slightly above the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate prolonged-release suspension for injection. Reversibility of these findings was not examined.