Paliperidone is an atypical antipsychotic that is a major active metabolite of risperidone (5-hydroxyrisperidone), approved for use in the US in 2006 as daily oral extended-release tablets and 1-month or 3-month LAI formulations
[2824][2925][3026]. Paliperidone ER is indicated for treatment of schizophrenia in adults and adolescents ages 12–17
[2824]. It is available in 1.5 mg, 3 mg, 6 mg, 9 mg and 12 mg
[2824]. The LAI form of paliperidone is indicated for the treatment of schizophrenia or schizoaffective disorder in adults as monotherapy or in conjunction with mood stabilizers, only after tolerance to oral paliperidone or risperidone has been demonstrated
[2925][3026]. The 3-month injectable is to be used only after successful administration of the 1-month LAI
[3026]. The 1-month LAI is available in dosages of 39 mg, 78 mg, 117 mg, 156 mg, or 234 mg and the 3-month injectable is available in the higher dosages of 273 mg, 410 mg, 546 mg, or 819 mg
[2925][3026]. Contraindications to the use of paliperidone include previous hypersensitivity reactions to paliperidone or risperidone
[2824][2925][3026]. Paliperidone, like all antipsychotics, is contraindicated for use in elderly patients with dementia-related psychosis, holding a boxed warning for increased mortality in this population
[2824][2925][3026]. Adverse events of paliperidone are consistent with other atypical antipsychotics due to dopamine blockade and effects at other neurotransmitter receptors. These include cerebrovascular disease (in the elderly), neuroleptic malignant syndrome, QT prolongation, extrapyramidal symptoms, tardive dyskinesia, weight gain, dyslipidemia, hyperglycemia, hyperprolactinemia, orthostatic hypotension, leukopenia, cognitive impairment and seizures
[2824][2925][3026]. No teratogenic effects have been demonstrated, but there is increased risk for EPS and/or withdrawal symptoms in neonates exposed during pregnancy
[2824][2925][3026]. Coadministration of paliperidone ER tablets or LAI with risperidone has not been studied
[2824][2925][3026].
4. Mechanism of Action
Paliperidone is in the benzisoxazole derivative class of atypical antipsychotics (including risperidone, iloperidone and paliperidone) and acts in accordance with others in the class
[2824]. While the full mechanism of atypical antipsychotics is yet to be fully realized, common features of the class include affinity for dopamine D
2 and serotonin 5-HT
2A receptors
[3127]. Unlike typical antipsychotics, atypicals, in general, have a higher ratio of antagonism at 5-HT
2A than D
2 receptors and have varying effects on other receptors
[3127]. In addition to 5-HT
2A and D
2 antagonism, paliperidone has antagonistic effects at α
1 and α
2 adrenergic and H
1 histaminergic receptors
[3228]. It has no affinity for M
1 cholinergic or β adrenergic receptors
[3228]. Positron emission tomography has shown paliperidone to occupy 70–80% of D
2 receptors in striatal and temporal cortex with a median effective dose of 2.38 mg/day and 2.84 mg/day, respectively
[3329]. Despite being the major active metabolite, paliperidone’s affinity profile does not equal that of risperidone—paliperidone has a lower ratio of 5-HT
2A/D
2 antagonism, lower affinity for α
1 and α
2 receptors and higher affinity for H
1 receptors
[3430]. Paliperidone receptor antagonism has been demonstrated in rats to affect serotonergic and noradrenergic signaling differently than risperidone in vivo
[3531]. Additionally, molecular signaling events following receptor binding have been shown to be distinct when comparing paliperidone and risperidone
[3632]. Paliperidone also has been demonstrated to induce mitochondrial protein expression changes in the prefrontal cortex similar to lithium, suggesting it may have mood stabilizing properties
[3733]. The molecular changes observed included increased proteins associated with receptor signaling, oxidative phosphorylation, neurotransmitter release and synaptic plasticity
[3733].
5. Pharmacokinetics/Pharmacodynamics
5. Pharmacokinetics/Pharmacodynamics
Paliperidone ER is designed with an osmotically controlled-release system which allows for continuous drug delivery after oral administration and no initial titration
[2834]. Paliperidone itself is insoluble in water with a volume of distribution of 487 L and it has an oral bioavailability of 28%
[2834][3135]. Paliperidone ER reaches maximal concentration (C
max) in 24 h and increases in C
max and the area under the drug concentration vs time curve (AUC) are observed after a high-fat or high-calorie meal
[2834][3135]. Paliperidone ER demonstrates dose-response proportional AUC and C
max in the recommended dose range
[2834][3135]. The time to reach steady-state is 4–5 days and terminal half-life is 23 h
[2834][3135].
The LAI paliperidone palmitate is deposited and slowly hydrolyzed to paliperidone over time. The 1-month and 3-month injectable forms reach C
max in a median time of 13 days and 33 days, respectively, and both have higher C
max when a deltoid injection is used rather than gluteal
[2936][3037][3135]. For this reason, the initial two doses are given in the deltoid muscle to rapidly achieve therapeutic concentration
[2936][3037].
Paliperidone is minimally metabolized by the cytochrome P450 2D6 and cytochrome P450 3A4 enzymes; however, these are suggested to play a clinically irrelevant role overall
[2834][3135]. Paliperidone is excreted 59% into urine unmetabolized and 11% into feces
[2834][3135]. Divalproex sodium coadministration with paliperidone resulted in higher C
max and AUC of oral paliperidone
[2834]. Carbamazepine coadministration decreased paliperidone by increasing renal clearance of paliperidone
[2834]. Renal impairment resulted in decreased clearance of paliperidone by 32% in mild impairment (CrCl from 50 mL/min to <80 mL/min), 64% in moderate impairment (CrCl from 30 mL/min to <50 mL/min) and 71% in severe impairment (CrCl from 10 mL/min to <30 mL/min)
[2834]. Mild to moderate hepatic impairment does not alter the plasma concentration of unbound paliperidone
[2834]. Effects of renal or hepatic impairment have not been directly studied for the LAI paliperidone palmitate.