|Year : 2017 | Volume
| Issue : 1 | Page : 8-10
Pimavanserin – drug review
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||19-Jun-2017|
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Pimavanserin is a drug with a novel mechanism of action that has recently received approval management of patients with Parkinson's disease psychoses [PDP]. It is a 5HT2A inverse agonist that has been shown in a randomized controlled trial to be superior to placebo and also reasonably safe and effective. It significantly reduces positive symptoms seen in Parkinson's disease patients with psychosis with no evident impairment of motor function. It offers hope for patients and caregivers with this otherwise distressing and difficult to manage condition and has also paved the way for the use of 5HT2A inverse agonists in this condition.
Keywords: Dementia, Parkinson's disease, Pimavanserin
|How to cite this article:|
Gogtay N. Pimavanserin – drug review. Ann Indian Psychiatry 2017;1:8-10
| Introduction|| |
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and impacts approximately one percent of the elderly population. Three-fourths of patients with PD also are afflicted with dementia. Parkinson's disease psychosis (PDP), which includes hallucinations and delusions, is frequent and debilitating and is seen in about 50%–60% of patients with the condition. The uniqueness of PDP lies in the fact that it arises within a context of clear sensorium and full-fledged insight and can run a chronic course. Psychosis is largely seen in patients receiving treatment (psychoses are rarely seen in untreated PD patients), and both delusions and hallucinations are common. Delusions tend to be of a paranoid nature and can be particularly distressing both to the patient and caregiver and affect their quality of lives. The symptoms are also known to be associated with a poorer outcome.
Pimavanserin, a 5-hydroxytryptamine (5-HT)2A inverse agonist was given breakthrough therapy status in September 2014 by the US Food and Drug Administration and subsequently approved by the same regulator for the treatment of hallucinations and delusions due to PDP in April 2016. This review summarizes the process of development of the drug, clinical trials with it, its pharmacology and current place in the armamentarium of the management of PDP.
| Parkinson's Disease Psychoses and Its Management Before Pimavanserin|| |
PDP is believed to result from a complex interplay of extrinsic, intrinsic, drug-related, and disease-related factors. Of these, the main extrinsic causes are thought to be the medications used to treat the disease themselves. These include – dopamine receptor agonists (apomorphine, pramipexole, ropinirole, rotigotine), N-methyl-D-aspartate receptor antagonists (amantadine), levodopa combinations, monoamine oxidase inhibitors (selegiline, rasagiline), catechol-O-methyl transferase inhibitors (entacapone, tolcapone), and antimuscarinic drugs (orphenadrine, procyclidine, trihexyphenidyl).
The drug class that has been maximally used for the management of PDP is the atypical antipsychotics (quetiapine, olanzapine, aripiprazole, ziprasidone, and clozapine). All have been used in low doses and are associated with mixed benefits. In addition, they have alongside, black box warnings for increased morbidity and mortality when used in elderly, demented patients. While psychoses can usually be relieved by a reduction in PD drug doses or the total number of medications, this often leads to an unacceptable worsening of motor function. Thus, a drug to alleviate symptoms without worsening the motor symptoms would be of immense value.
| Rationale for Targeting the 5-Hydroxytryptamine2a Receptor|| |
The atypical antipsychotic clozapine in the dose range of 12.5–75 mg/day has been shown to be an effective and tolerable treatment option for PDP. Serious side effects such as agranulocytosis, however, mar its use. Meltzer et al. studied levels of clozapine and its metabolite in patients with PDP who were classified as “responders” and found in them levels in the range of 4.5 and 16.1 ng/ml and that of the metabolite N-desmethylclozapine in the range of 2.6 and 6.1 ng/ml. These levels were far lower than the usual levels of 100–687 ng/ml seen in patients treated with clozapine for refractory schizophrenia or affective disorders. They suggested a potential inverse agonist effect (an inverse agonist is one that binds to the receptor in a manner similar to the agonist, but produces an action that is exactly the opposite) of clozapine at 5-HT2A receptors at low doses as the potential explanation for the drug's efficacy. It was also hypothesized that these inverse agonists would provide adequate symptom relief along with reasonable safety and tolerability profile. The discovery of Pimavanserin was the result of a high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists.
| The 5-Hydroxytryptamine (Serotonin) Receptor Family|| |
Radioligand-binding technology enabled the identification of multiple distinct serotonin receptors based principally on their differential radioligand-binding properties. The 5HT or serotonin receptor family has a total of 14 distinct receptors and is divided into seven receptor families (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7) with a potential receptor (5-HT1P) awaiting classification. With the exception of 5HT3, all the others are G-protein coupled receptors. These receptors serve as therapeutic targets for several neuropsychiatric disorders that include anxiety, depression, and schizophrenia obesity, migraine headaches, chemotherapy-induced nausea, and even Alzheimer's disease. A wide range of drugs that target these receptors have been developed, and these include full agonists, partial agonists, antagonists, and inverse agonists.
The 5-HT2A receptor (the target of Pimavanserin) is largely excitatory in nature and is widely distributed throughout the central nervous system with the highest density within the cerebral cortex. Psychedelic drugs like LSD mediate their hallucinogenic effects through this receptor. The psychiatric adverse events of the anti-HIV drug efavirenz are also mediated through this receptor. Trazodone, mirtazapine, and atypical antipsychotics such as clozapine are antagonists at this receptor.
| Pimavanserin-Mechanism of Action and Pharmacokinetics|| |
Pimavanserin is a potent 5-HT2A inverse agonist and 5-HT2C inverse agonist, with 5-fold greater affinity for the 5-HT2A receptor. It blocks the basal (constitutive activity]) of the 5-HT2A receptor and also has some though limited antagonistic action at the receptor. Uniquely, it does not bind to dopamine, histamine, muscarinic, or adrenergic receptors thus is not associated with side effects such as anticholinergic effects, orthostasis, or sedation that are commonly seen with the use of atypical antipsychotics. The drug has linear pharmacokinetics.
| Pimavanserin-Efficacy and Safety|| |
In a pivotal study conducted over 6 weeks, patients with PD were randomized in a 1:1 ratio to receive either Pimavanserin (40 mg/day) or a matched placebo. Antipsychotics were not permitted during the study though antiparkinsonian medication was. A total of n = 95 patients on Pimavanserin and n = 90 on placebo were eventually analyzed. Antipsychotic benefit was assessed by central, independent raters using a PD-adapted scale for assessment of positive symptoms. Relative to placebo, Pimavanserin significantly reduced positive symptoms seen in PD patients with psychosis with no evident impairment of motor function. Only two adverse effects occurred in ≥5% of Pimavanserin-treated patients and at ≥2 times the rate of placebo: peripheral edema (7% for Pimavanserin vs. 3% for placebo) and confusion (6% for Pimavaserin vs. 3% for placebo). There was though a mean increase in the QTc of 7.3 ms compared with placebo during this pivotal Phase III study.
| Interactions, Safety, and Dosing|| |
As the drug can prolong the QT interval, it should be used with caution in other drugs that prolong QT interval and in patients with risk factors for QT prolongation (e.g. symptomatic bradycardia, hypokalemia, hypomagnesemia, congenital prolongation of the QT interval, use of antiarrhythmics). When used with drugs that inhibit CYP3A4 (e.g. ketoconazole), the dose of Pimavanserin should be reduced. When used with drugs that induce CYP3A4 (rifampicin), the efficacy should be monitored, and the dose may be stepped up. Dose modification is not required in mild and moderate renal impairment. The drug is not recommended for use in severe renal dysfunction as also hepatic impairment (the drug has not undergone studies in hepatic dysfunction). The current recommended dose is 34 mg once a day (two tablets of 17 mg) without titration, with or without food. Treating physicians should watch for peripheral edema and confusional states; the two most commonly observed adverse events in clinical trials. The drug comes with a boxed warning of increased mortality in elderly patients with dementia-related psychoses and is not approved for this indication. It has also not been evaluated in the pediatric population.
| Ongoing Studies With Pimavanserin|| |
Further to its approval for the management of PDP, the drug is undergoing clinical trials for several other indications. An analysis of the clinical trials registry https://clinicaltrials.gov/is given in [Table 1] where studies with Pimavanserin along with indications are listed.
| Conclusions|| |
Pimavanserin has shown both reasonable safety and efficacy in patients with PDP. An open-label extension study has further demonstrated that Pimavanserin is safe and well-tolerated with long-term use. This drug may therefore offer a viable treatment option for patients suffering from PDP and also pave the way for the use of 5-HT2A inverse agonists for the management of this difficult condition. Its unique mode of action has also paved the way for studies in other conditions such as schizophrenia, major depressive disorder, and Alzheimer's disease and the next few years are likely to witness an expansion of the drug's indications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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