Tolerability
The discontinuation rate because of adverse events for pimavanserin and placebo-treated patients was 10 patients in the pimavanserin group (4 due to psychotic symptoms within 10 days of starting the study drug) compared with 2 in the placebo group. There was no evidence of motor worsening in either group, demonstrated by the score on part II of the Unified Parkinson’s Disease Rating Scale (UPDRS) that captures self-reported activities of daily living, or on UPDRS part III (motor examination). Pimavanserin has no contraindications.
Unique clinical issues
Binding properties. Pimavanserin possesses potent 5-HT2A inverse agonist properties required to manage psychosis in PD patients, but lacks clozapine’s affinities for α-1 adrenergic, muscarinic, or histaminergic receptors that contribute to clozapine’s poor tolerability. Moreover, pimavanserin has no appreciable affinity for dopaminergic receptors, and therefore does not induce motor adverse effects.
Clozapine aside, all available atypical antipsychotics have proved ineffective for psychosis in PD patients, and most caused significant motor worsening.3 Although quetiapine does not cause motor effects, it has been shown to be ineffective for psychosis in PD patients in multiple trials.4
The effect size for clozapine response is large (0.80) in PD patients with psychosis, but tolerability issues and administrative burdens regarding patient and prescriber registration and routine hematological monitoring pose significant clinical barriers. Clozapine also lacks an FDA indication for this purpose, which may pose a hurdle to its use in certain treatment settings.
Why Rx? The reasons to prescribe pimavanserin for PD patients with psychosis likely include:
- absence of tolerability issues seen with the only other effective agent, clozapine
- lack of motor effects
- lack of administrative and monitoring burden related to clozapine prescribing
- only agent with FDA approval for hallucinations and delusions in PD patients with psychosis.
Dosing
The recommended dosage of pimavanserin is 34 mg/d administered as a single dose with or without food. There is no need for titration, and none was performed in the pivotal clinical trial. Given the long half-life (57 hours), steady state is not achieved until day 12, therefore initiation with a lower dosage might prolong the time to efficacy. There is no dosage adjustment required in patients with mild or moderate renal impairment, but pimavanserin treatment is not recommended in patients with severe renal impairment. Pimavanserin has not been evaluated in patients with hepatic impairment (using Child-Pugh criteria), and is not recommended for these patients.
Other key aspects of dosing to keep in mind.
- Because pimavanserin is metabolized primarily by CYP3A4, dosage adjustment is required in the presence of a strong CYP3A4 inhibitor; the recommended dosage is 17 mg/d when administered concomitantly with a strong CYP3A4 inhibitor.
- Because data are not available regarding concomitant use of pimavanserin with CYP3A4 inducers, patients should be monitored for lack of efficacy during concomitant use with a CYP3A4 inducer, and consideration given to a dosage increase.
Use in pregnancy and lactation. There are no data on the use of pimavanserin in pregnant women, but no developmental effects were seen when the drug was administered orally at 10 or 12 times the maximum recommended human dosage to rats or rabbits during organogenesis. Pimavanserin was not teratogenic in pregnant rats and rabbits. There is no information regarding the presence of pimavanserin in human breast milk.
Geriatric patients. No dosage adjustment is required for older patients. The study population in the pivotal trial was mean age 72.4 years.
Summing up
Before development of pimavanserin, clozapine was the only effective treatment for psychosis in PD patients. Despite clozapine’s robust effects across several trials, patients often were given ineffective medications, such as quetiapine, because of the administrative and tolerability barriers posed by clozapine use. Because psychosis is the most common cause of nursing home placement in non-demented PD patients, an agent with demonstrated efficacy and without the adverse effect profile of clozapine or monitoring requirements represents an enormous advance in the treatment of psychosis in PD patients.