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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 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 DRUG INTERACTIONS ]. 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, best steroid for lean muscle and strength. 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 TRINZA ‘ on the exposures of other drugs are summarized in Figure 2. After oral administration of paliperidone, the steady-state Cmax 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 DRUG INTERACTIONS ]. 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 and Use In Specific Populations ]. 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 ]. After oral administration of paliperidone in elderly subjects, the Cmax and AUC increased 1. However, there may be age-related decreases in creatinine clearance [see DOSAGE AND ADMINISTRATION and Use In Specific Populations ]. Figure 3: Effects of intrinsic factors on paliperidone pharmacokinetics. 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. 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.
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