FDA Approves NUPLAZID® (Pimavanserin) for the Treatment of Hallucinations and Delusions Associated With Parkinson’s Disease Psychosis
On April 29, 2016, the FDA approved NUPLAZID (pimavanserin) immediate release tablets for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. The approved recommended dosage is 34 mg without titration, taken as two 17 mg tablets once daily with or without food.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis.
Mechanism of Action, General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Pimavanserin
The mechanism of action of pimavanserin in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis is unknown. But the effect of pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5- HT2C receptors. Pimavanserin has no appreciable affinity (Ki value greater than 300 nM) to serotonin 5- HT2B, dopaminergic (including D2), muscarinic, histaminergic or adrenergic receptors or to calcium channels.
- Dose Proportionality: Dose proportional PK after single oral doses from 17 to 255 mg (0.5- to 7.5-times the recommended dosage)
- Accumulation: approximately 3- to 5-fold after multiple doses for 14 days.
- Bioavailability: The relative bioavailability of pimavanserin tablet with an investigational solution formulation as reference is essentially identical. The absolute bioavailability was not determined.
- Plasma Protein Binding: Approximately 95% in human plasma.
- Terminal Half-Life (mean): Pimavanserin- 57 hours; N-desmethylated metabolite (active) – 200 hours.
- Metabolism: Extensive. Predominantly by Cytochrome P450 (CYP)3A and to a lesser extent by CYP2J2, CYP2D6, and various other CYP and flavin-containing monooxygenase (FMO) enzymes. The CYP3A mediated formation of the major circulating N-desmethylated metabolite AC-279 (active) from pimavanserin occurs with a median Tmax of 6 hours.
- Excretion: The majority of an orally administered radioactive pimavanserin dose is excreted in feces as metabolites. Approximately 0.55% and 1.53% of unchanged pimavanserin is eliminated in urine and feces, respectively. Less than 1% of administered dose of pimavanserin and its active metabolite (N-desmethylated metabolite) are excreted in urine.
- Exposure-safety: A PK/PD analysis with NUPLAZID suggested a concentration-dependent QTc interval prolongation in the therapeutic range. 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. In effectiveness studies, mean increases in QTc interval of approximately 5-8 msec were observed in patients receiving once-daily doses of NUPLAZID 34 mg.
Drug Interaction Potential
- Co-administration of NUPLAZID with ketoconazole, a strong CYP3A inhibitor, increased pimavanserin Cmax by 1.5-fold and AUC by 3-fold. The recommended dose of NUPLAZID when coadministered with strong CYP3A4 inhibitors is 17 mg, taken orally as one tablet once daily.
- Co-administration of NUPLAZID with a strong CYP3A4 inducer may reduce pimavanserin Cmax and AUC resulting in a potential decrease in efficacy. Monitor patients for reduced efficacy if NUPLAZID is used concomitantly with strong CYP3A4 inducers; an increase in NUPLAZID dosage may be needed.
- Co-administration of NUPLAZID with carbidopa/levodopa or midazolam (CYP3A substrate) did not have a clinically significant effect on levodopa or midazolam Cmax or AUC.
- Based on in vitro studies, transporters play no significant role in the disposition of pimavanserin.
Use in Specific Populations
- The effect of hepatic impairment on pimavanserin PK is unknown. Pimavanserin is not recommended for patients with hepatic impairment.
- The effect of renal impairment (CrCl less than 30 mL/min, as estimated by Cockcroft-Gault (C-G) method) on pimavanserin PK is unknown. Pimavanserin is not recommended for patients with severe renal impairment.
- A clinically significant effect on pimavanserin PK was not observed in patients with the following characteristics: mild to moderate renal impairment (CrCl greater than or equal to 30 mL/min, C-G), body weight, height, and age (18 to 89 years of age).
Safety and Efficacy
NUPLAZID, at the approved recommended dosage, was statistically significantly superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions in patients with Parkinson's disease psychosis (PDP) based upon the Parkinson’s disease (PD) adapted Scale for Assessment of Positive Symptoms (SAPS-PD) in a 6-week clinical trial. The SAPS-PD is a 9-item scale adapted for PD from the hallucinations and delusions domains of the Scale for Assessment of Positive Symptoms (SAPS). Nuplazid did not show an effect compared to placebo on motor function, as measured using the Unified Parkinson’s Disease Rating Scale Parts II and III (UPDRS II + III), in patients with hallucinations and delusions associated with PDP. The most common adverse events (incidence greater than or equal to 5% and at least twice the rate of placebo) were peripheral edema and confusional state. The adverse events that occurred in more than one patient and with an incidence twice that of placebo that led to discontinuation of Nuplazid at the recommended approved dosage were hallucinations, urinary tract infection and fatigue.
Full prescribing information is available at http://go.usa.gov/cSRsH.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/
report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency’s Drugs@FDA website (http://go.usa.gov/cSRH4)
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The burst was prepared by the Clinical Pharmacology Review Team of Kofi Kumi, Ph.D., Di Zhou, Ph.D., Kevin Krudys, Ph.D*. and Hao Zhu, Ph.D., Division of Clinical Pharmacology 1 and *Division of Pharmacometrics, Office of Clinical Pharmacology/OTS
FDA/Center for Drug Evaluation and Research (CDER)
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Office of Clinical Pharmacology
Office of Translational Sciences
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