How it works
The theory behind development of pimavanserin rests in the finding that low-dosage clozapine (6.25 to 50 mg/d) was effective for PD patients with psychosis (effect size 0.80).8 Although clozapine has high affinity for multiple sites, including histamine H1 receptors (Ki = 1.13 nM), α-1A and a α-2C adrenergic receptors (Ki = 1.62 nM and 6 nM, respectively), 5-HT2A receptors (Ki = 5.35 nM), and muscarinic M1 receptors (Ki = 6 nM), the hypothesized primary mechanism of clozapine’s effectiveness for PD psychosis at low dosages focused on the 5-HT2Areceptor. This idea was based on the knowledge that hallucinogens such as mescaline, psilocybin, and LSD are 5-HT2A agonists.9 This hallucinogenic activity can be blocked with 5-HT2A antagonists. Because of pimavanserin’s binding profile, the compound was studied as a treatment for psychosis in PD patients.
Pharmacokinetics
Pimavanserin demonstrates dose-proportional pharmacokinetics after a single oral dose as much as 7.5 times the recommended dosage. The pharmacokinetics of pimavanserin were similar in study participants (mean age, 72.4) and healthy controls, and a high-fat meal had no impact on the maximum blood levels (Cmax) or total drug exposure (area under the curve [AUC]).
The mean plasma half-lives for pimavanserin and its metabolite N-desmethyl-pimavanserin (AC-279) are 57 hours and 200 hours, respectively. Although the metabolite appears active in in vitro assays, it does not cross the blood-brain barrier to any appreciable extent, therefore contributing little to the clinical effect. The median time to maximum concentration (Tmax) of pimavanserin is 6 hours with a range of 4 to 24 hours, while the median Tmax of the primary metabolite AC-279 is 6 hours. The bioavailability of pimavanserin in an oral tablet or solution essentially is identical.
Pimavanserin is primarily metabolized via CYP3A4 to AC-279, and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, indinavir) increase pimavanserin Cmax by 1.5-fold, and AUC by 3-fold. In patients taking strong CYP3A4 inhibitors, the dosage of pimavanserin should be reduced by 50% to 17 mg/d. Conversely, patients on CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin) should be monitored for lack of efficacy; consider a dosage increase as necessary. Neither pimavanserin nor its metabolite, AC-279, are inhibitors or inducers of major CYP enzymes or drug transporters.
Efficacy in PD psychosis
Study 1. This 6-week, fixed dosage, double-blind, placebo-controlled trial was performed in adult PD patients age ≥40 with PD psychosis.2 Participants had to have (1) a PD diagnosis for at least 1 year and (2) psychotic symptoms that developed after diagnosis. Psychotic symptoms had to be present for at least 1 month, occurring at least weekly in the month before screening, and severe enough to warrant antipsychotic treatment. Baseline Mini-Mental State Examination score had to be ≥21 out of 30, with no evidence of delirium. Patients with dementia preceding or concurrent with the PD diagnosis were excluded. Antipsychotic treatments were not permitted during the trial.
After a 2-week nonpharmacotherapeutic lead-in phase that included a brief, daily psychosocial intervention by a caregiver, 199 patients who still met severity criteria were randomly allocated in a 1:1 manner to pimavanserin (34 mg of active drug, reported in the paper as 40 mg of pimavanserin tartrate) or matched placebo. Based on kinetic modeling and earlier clinical data, lower dosages (ie, 17 mg) were not explored, because they achieved only 50% of the steady state plasma levels thought to be required for efficacy.
The primary outcome was assessed by central, independent raters using the PD-adapted SAPS-PD. The efficacy analysis included 95 pimavanserin-treated individuals and 90 taking placebo. Baseline SAPS-PD scores were 14.7 ± 5.55 in the placebo group, and 15.9 ± 6.12 in the pimavanserin arm. Participants had a mean age of 72.4 and 94% white ethnicity across both cohorts; 42% of the placebo group and 33% of the pimavanserin group were female. Antipsychotic exposure in the 21 days prior to study entry were reported in 17% (n = 15) and 19% (n = 18) of the placebo and pimavanserin groups, respectively, with the most common agent being quetiapine (13 of 15, placebo, 16 of 18, pimavanserin). Approximately one-third of all participants were taking a cholinesterase inhibitor throughout the study.
Efficacy outcome. Pimavanserin was associated with a 5.79-point decrease in SAPS-PD scores compared with 2.73-point decrease for placebo (difference −3.06, 95% CI −4.91 to −1.20; P = .001). The effect size for this difference (Cohen’s d) was 0.50. The significant effect of pimavanserin vs placebo also was seen in separate analyses of the SAPS-PD subscore for hallucinations and delusions (effect size 0.50), and individually for hallucinations (effect size 0.45) and delusions (effect size 0.33). Separation from placebo appeared after the second week of pimavanserin treatment, and continued through the end of the study. There is unpublished data showing efficacy through week 10, and longer term, uncontrolled data consistent with sustained response. An exploratory analysis of caregiver burden demonstrated an effect size of 0.50.