TREVICTA® 525MG

Indications

• Schizophrenia
• Schizoaffective disorder

Dosage

Children: For children and adolescents

Adults: For adults, the initial dosage is typically 3 to 12 mg once daily, with adjustments made based on the clinical response and tolerability. For long-acting injectable formulations, the initial dose may range from 175 to 525 mg every 3 months, depending on previous treatment with paliperidone.

Mechanism of action

Paliperidone exerts its therapeutic activity primarily through antagonism of central dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptors. Although the exact mechanism of action is not fully understood, it is proposed that this dual receptor antagonism contributes to its efficacy in treating schizophrenia. Additionally, paliperidone may also interact with alpha-adrenergic and histamine (H1) receptors, influencing various therapeutic and adverse effects.

Pharmacodynamics

As an atypical antipsychotic, paliperidone is designed to address the symptoms of schizophrenia and schizoaffective disorder. It is chemically similar to risperidone, with a structure that includes a hydroxyl group modification. Its pharmacodynamic profile is characterized by a lower propensity to cause extrapyramidal symptoms compared to first-generation antipsychotics, potentially due to its receptor binding profile, which includes a greater affinity for serotonin receptors relative to dopamine receptors.

Pharmacokinetics

Paliperidone has a bioavailability of approximately 28% when administered orally. It is extensively metabolized in the liver, primarily via the CYP2D6 pathway, and has an elimination half-life of around 23 hours. The drug is excreted mainly through urine, and its pharmacokinetics can be influenced by factors such as renal impairment. In cases of renal impairment, dosage adjustments are necessary to avoid accumulation and potential toxicity.

Contra-indications

• Hypersensitivity to paliperidone or any component of the formulation
• Severe renal impairment (creatinine clearance < 10 mL/min)

Adverse effects

• Extrapyramidal symptoms
• Sedation
• Weight gain
• Hyperglycemia
• Hyperlipidemia
• QT prolongation
• Severe cutaneous adverse reactions (SCARs)
• Injection site necrosis (with intramuscular use)

Interactions

• Valproate: Moderate (increases exposure)
• Mitotane: Moderate (decreases exposure)
• Rifampicin: Moderate (decreases exposure)
• St. John's Wort: Unknown (decreases exposure)

Precautions

• Caution in patients with a history of seizures
• Caution in patients with diabetes mellitus
• Monitor for signs of tardive dyskinesia
• Gradual withdrawal is advised to prevent withdrawal syndrome
• Caution in hepatic impairment (no specific information available)

Pregnancy

Manufacturer advises avoiding use during pregnancy unless necessary, as safety has not been established.

Breast-feeding

Manufacturer advises avoiding use while breastfeeding, as paliperidone is present in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets: 1.5 mg, 3 mg, 6 mg, 9 mg
• Long-acting injection (TREVICTA): 175 mg, 263 mg, 350 mg, 525 mg

Mechanism of action

Excessive palmitoylcarnitine formation and exhausted L-carnitine stores lead to energy depletion, which, along with attenuated acetylcholine synthesis and oxidative stress, are main mechanisms behind palmitate-induced neuronal loss. High levels of palmitate exposure are suggested to contribute to diabetic neuropathy and gastrointestinal dysregulation. Additionally, palmitate negatively regulates acetyl-CoA carboxylase, thereby preventing further palmitate generation.

Pharmacodynamics

Palmitate is the first fatty acid generated during lipogenesis and serves as a precursor for the synthesis of longer fatty acids. The presence of palmitate inhibits acetyl-CoA carboxylase, reducing the conversion of acetyl-ACP to malonyl-ACP, which subsequently decreases the synthesis of new palmitate. This feedback mechanism is crucial for maintaining lipid homeostasis within the body.

Pharmacokinetics

Palmitate is absorbed from dietary sources and can also be synthesized endogenously in the liver and adipose tissue. Once in circulation, it is transported via chylomicrons or albumin. The metabolism of palmitate occurs primarily in the mitochondria through fatty acid oxidation, generating acetyl-CoA, which can enter the citric acid cycle for energy production. The overall kinetics of palmitate are influenced by dietary intake, metabolic demand, and hormonal regulation.

Pregnancy

Palmitate is classified as a category C drug. Animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

There are no data on the excretion of palmitate in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Keep the container tightly closed.

Formulations

• Palmitate 500 mg softgel
• Palmitate 1000 mg softgel

Mechanism of action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.1 39 41 Antagonism at a1- and a2-adrenergic and histamine (H1) receptors may contribute to other therapeutic and adverse effects observed with the drug.1 2 39 Paliperidone possesses no affinity for cholinergic muscarinic and beta1- and beta2-adrenergic receptors. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. Paliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. /The researchers/ compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D2 , human serotonin 2A receptor subtype (5-HT2A ), human serotonin 2C receptor subtype and human histamine H1 receptors. Whereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT2A -mediated recruitment of beta-arrestin, 5-HT2A -mediated sensitization of ERK, and dopamine D2 -mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. These results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects.

Pharmacodynamics

Paliperidone is an atypical antipsychotic developed by Janssen Pharmaceutica. Chemically, paliperidone is primary active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone). The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone.

Mechanism of action

... Excessive palmitoylcarnitine formation and exhausted L-carnitine stores leading to energy depletion, attenuated acetylcholine synthesis and oxidative stress to be main mechanisms behind PA-induced neuronal loss.High PA exposure is suggested to be a factor in causing diabetic neuropathy and gastrointestinal dysregulation. ... First phase insulin release response was lost in these islets. FFAs slightly increased the insulin output of normal fresh pancreas beta-cells. However, chronic exposure to FFAs resulted in loss of first phase insulin release and blunted insulin secretion response to various levels of D-glucose stimulation.

Pharmacodynamics

Palmitic acid is the first fatty acid produced during lipogenesis (fatty acid synthesis) and from which longer fatty acids can be produced. Palmitate negatively feeds back on acetyl-CoA carboxylase (ACC) which is responsible for converting acetyl-ACP to malonyl-ACP on the growing acyl chain, thus preventing further palmitate generation