PIMVAN 34

Indications

• Hallucinations associated with Parkinson's disease psychosis
• Delusions associated with Parkinson's disease psychosis

Dosage

Adults: The recommended dose for adults is 34 mg once daily. It should be taken without regard to food.

Mechanism of action

Pimavanserin is primarily an inverse agonist and antagonist at serotonin 5-HT2A receptors, with a high binding affinity, while it shows limited activity at serotonin 5-HT2C receptors. This serotonergic modulation helps restore the balance between serotonin and dopamine, which is disrupted in Parkinson's disease psychosis. Additionally, pimavanserin has low affinity for sigma 1 receptors and does not bind appreciably to muscarinic, dopaminergic, adrenergic, or histaminergic receptors, minimizing the risk of typical antipsychotic side effects.

Pharmacodynamics

Pimavanserin's specific actions on serotonin receptors have been shown to improve symptoms of hallucinations and delusions in patients with Parkinson's disease. Clinical studies indicate that approximately 80.5% of patients treated with pimavanserin experience symptom improvement. Importantly, pimavanserin does not impair motor function in patients, making it a favorable treatment option for those suffering from PDP.

Pharmacokinetics

Pimavanserin exhibits a relatively long half-life, allowing for once-daily dosing. It is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, particularly CYP3A4. The elimination of pimavanserin is primarily via fecal excretion. Due to its pharmacokinetic profile, dose adjustments may be necessary in the presence of strong CYP3A4 inhibitors or in patients with hepatic impairment.

Adverse effects

• Somnolence
• Confusion
• Peripheral edema
• Nausea

Precautions

• Use with caution in patients with a history of cardiovascular disease.
• Monitor closely for signs of worsening psychiatric symptoms.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Pimavanserin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether pimavanserin is excreted in human milk. Caution should be exercised when administering to nursing women.

Storage

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

Formulations

• Tablets: 34 mg

Mechanism of action

Parkinson's disease psychosis (PDP) is an imbalance of serotonin and dopamine from disruption of the normal balance between the serotonergic and dopaminergic receptors and neurotransmitters in the brain. The mechanism by which pimavanserin treats hallucinations and delusions associated with Parkinson’s disease psychosis is not fully established. It is possible that pimavanserin acts via inverse agonist and antagonist activity at serotonin 5-HT_2A receptors with limited effects on serotonin 5-HT_2C receptors. Pimavanserin is an inverse agonist and antagonist of serotonin 5-HT_2A receptors with high binding affinity, demonstrating low binding affinity to serotonin 5-HT_2C receptors. In addition, this drug exhibits low affinity binding to sigma 1 receptors. Pimavanserin lacks activity at muscarinic, dopaminergic, adrenergic, and histaminergic receptors, preventing various undesirable effects typically associated with antipsychotics.

Pharmacodynamics

Pimavanserin's unique actions on serotonin receptors improve symptoms of hallucinations and delusions associated with Parkinson's disease. In clinical studies, 80.5% of individuals treated with pimavanserin reported improvement in symptoms. Pimavanserin does not worsen motor functioning in patients with Parkinson's disease psychosis. In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT_2A receptors with high binding affinity (K_i value 0.087 nM) and at serotonin 5-HT_2C receptors with lower binding affinity (K_i value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (K_i value 120 nM) and has no appreciable affinity (K_i value >300 nM), to serotonin 5-HT_2B, dopaminergic (including D₂), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels. The effect of pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/pharmacodynamic analysis with pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range. In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with pimavanserin 34 mg; although the incidence was generally similar for pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of pimavanserin, including those patients with hallucinations and delusions associated with Parkinson’s disease psychosis.