Absorption and Distribution

Due to its extremely low water solubility, the 3-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 lasts for as long as 18 months.

Following a single intramuscular dose of INVEGA TRINZA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median T maxof 30–33 days. Following intramuscular injection of INVEGA TRINZA at doses of 273–819 mg in the deltoid muscle, on average, an 11–12% higher C maxwas observed compared with injection in the gluteal muscle. The release profile and dosing regimen of INVEGA TRINZA results in sustained therapeutic concentrations over 3 months. The total and peak exposure of paliperidone following INVEGA TRINZA administration was dose-proportional over a 273–819 mg dose range. The mean steady-state peak:trough ratio for a INVEGA TRINZA dose was 1.6 following gluteal administration and 1.7 following deltoid administration. Following administration of INVEGA TRINZA, the apparent volume of distribution of paliperidone is 1960 L. 

The plasma protein binding of racemic paliperidone is 74%.

Following administration of INVEGA TRINZA, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7–1.8.

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 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. The concentration of paliperidone remaining in the circulation 18 months after dosing of 819 mg INVEGA TRINZA is stopped is estimated to be 3% (following deltoid injection) or 7% (following gluteal injection) of the average steady-state levels.

Long-acting 3-month paliperidone palmitate injection versus other paliperidone formulations

INVEGA TRINZA is designed to deliver paliperidone over a 3-month period, while 1-month paliperidone palmitate injection is administered on a monthly basis. INVEGA TRINZA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-month paliperidone palmitate injection, results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-month paliperidone palmitate injection and corresponding once daily doses of paliperidone extended-release tablets. The exposure range for INVEGA TRINZA is encompassed within the exposure range for the approved dose strengths of paliperidone extended-release tablets.

The between-subject variability for paliperidone pharmacokinetics following delivery from INVEGA TRINZA was similar to the variability for paliperidone extended-release tablets. Because of the difference in median pharmacokinetic profiles among the three formulations, 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 TRINZA. The information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of INVEGA TRINZA 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 INVEGA TRINZA pharmacokinetics. 

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. 

The effects of INVEGA TRINZA on the exposures of other drugs are summarized in Figure 2.

After oral administration of paliperidone, the steady-state C maxand 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 Drug Interactions (7.1)] . 

Figure 2:The effects of INVEGA TRINZA on pharmacokinetics of other drugs. 

Studies in Specific Populations

No specific pharmacokinetic studies have been performed with INVEGA TRINZA 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 TRINZA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [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 3: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 TRINZA, the trough concentrations were similar between males and females. 

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