Absorption and Distribution

Due to its extremely low water solubility, the 1-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T maxof 13 days. The release of the drug starts as early as day 1 and lasts for as long as 126 days. 

Following intramuscular injection of single doses (39 mg – 234 mg) in the deltoid muscle, on average, a 28% higher C maxwas observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 234 mg on day 1 and 156 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of INVEGA SUSTENNA results in sustained therapeutic concentrations. The AUC of paliperidone following INVEGA SUSTENNA administration was dose-proportional over a 39 mg-234 mg dose range, and less than dose-proportional for C maxfor doses exceeding 78 mg. The mean steady-state peak:trough ratio for an INVEGA SUSTENNA dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration. 

Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6–1.8.

Based on a population analysis, the apparent volume of distribution of paliperidone is 391 L. The plasma protein binding of racemic paliperidone is 74%.

Metabolism and Elimination

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 vitrostudies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivothat 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. 

The median apparent half-life of paliperidone following INVEGA SUSTENNA single-dose administration over the dose range of 39 mg – 234 mg ranged from 25 days – 49 days.

Long-Acting Paliperidone Palmitate Injection versus Oral Extended-Release Paliperidone

INVEGA SUSTENNA is designed to deliver paliperidone over a monthly period while extended-release oral paliperidone is administered on a daily basis. The initiation regimen for INVEGA SUSTENNA (234 mg/156 mg in the deltoid muscle on Day 1/Day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.

In general, overall initiation plasma levels with INVEGA SUSTENNA were within the exposure range observed with 6–12 mg extended-release oral paliperidone. The use of the INVEGA SUSTENNA initiation regimen allowed patients to stay in this exposure window of 6–12 mg extended-release oral paliperidone even on trough pre-dose days (Day 8 and Day 36). The intersubject variability for paliperidone pharmacokinetics following delivery from INVEGA SUSTENNA was lower relative to the variability determined from extended-release oral paliperidone tablets. Because of the difference in median pharmacokinetic profiles between the two products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.

Drug Interaction Studies

No specific drug interaction studies have been performed with INVEGA SUSTENNA. The information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C maxand AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean C maxand AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. 

Figure 1: The effects of other drugs on paliperidone pharmacokinetics.

Clinically meaningful pharmacokinetic interaction between INVEGA SUSTENNA and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the C maxand AUC of paliperidone. 

After oral administration of paliperidone, the steady-state C maxand AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended-release tablets. In a clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3–15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)] . 

In vitrostudies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivothat inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitrostudies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)] . 

In vitrostudies 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 vivodata are available, and the clinical relevance is unknown. 

Studies in Specific Populations

No specific pharmacokinetic studies have been performed with INVEGA SUSTENNA 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 SUSTENNA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 2 [see Dosage and Administration (2.5)and Use in Specific Populations (8.6)] . 

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 Use in Specific Populations (8.7)] . 

After oral administration of paliperidone in elderly subjects, the C maxand AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.5)and Use in Specific Populations (8.5)] . 

Figure 2: Effects of intrinsic factors on paliperidone pharmacokinetics.

Based on in vitrostudies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. 

Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with INVEGA SUSTENNA, the trough concentrations were similar between males and females.

Lower C maxwas observed in overweight and obese subjects. At apparent steady-state with INVEGA SUSTENNA, the trough concentrations were similar among normal, overweight, and obese subjects.