Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 17 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 effective addition to the PDP armamentarium and in 2016 became the first drug to receive FDA approval for PDP treatment. 14 This article reviews the pharmacology, efficacy, and safety data available for pimavanserin and provides comparison with other therapeutic options to suggest its likely role in treatment of PDP. METHODS Initial literature sources were identified via MEDLINE search (1946–September 2016) of pimavanserin and ACP-103 (the original molecular designation of pimavanserin). Reference review and search of FDA and Acadia® websites and yielded additional unpublished data. English- language studies of pimavanserin for PDP were evaluated. Animal studies were excluded. Priority was given to randomized, controlled trials (RCTs). Abstracts of identified studies were screened for eligibility, initially by two reviewers, with 100-percent agreement. A third reviewer assessed the included studies post-agreement by the initial reviewers. Details of the trials were extracted into a spreadsheet. The data were summarized with regard to the drug's pharmacology, pharmacokinetics, clinical trial data, dosing, adverse effects, precautions, contraindications, monitoring, and drug interactions. RESULTS Pharmacology . The primary pathology in PD is dopamine deficiency in the basal ganglia, which results in the characteristic motor dysfunction. 7 Dopaminergic neuronal degeneration in the nigrostriatal pathway produces overall increased inhibitory signaling to the thalamus and motor cortex, thus resulting in bradykinesia, muscular rigidity, resting tremor, and postural instability. 15 Though development of PDP likely involves multiple systems, including dopaminergic, glutamatergic, cholinergic, and serotonergic systems, some researchers have hypothesized that dopamine deficiency precipitates up-regulation of 5-HT function and receptor sensitivity, especially in the visual processing circuitry. This can result in psychosis with prominent VH, most commonly with insight. 7,9,13,16,17 Of particular interest are 5-HT 2A receptors, as brain imaging scans of patients with PD with VH display increased 5-HT 2A binding in the brain's visual processing areas. 17,18 Medications currently used off-label to treat PDP display prominent 5-HT 2 receptor binding at low doses, consistent with this theory. 7,16 Pimavanserin primarily functions as an inverse agonist and antagonist (a partial inverse agonist) at 5-HT 2A receptors. 12 Selectivity for 5-HT 2 receptors and sparing the dopamine post-synaptic receptors differentiates pimavanserin from other antipsychotic drugs currently used in PDP. 16 Pimavanserin binds with high affinity (Ki 0.087nM) to 5-HT 2A and five-fold lower affinity (Ki 0.44nM) to 5-HT 2C , with negligible binding at 5-HT 2B , dopaminergic (D 3 ), muscarinic (M 5 ), and opioid (sigma 1) receptors. 19 First- generation antipsychotics should be avoided in PDP, as their extensive dopamine (D 2 ) receptor antagonism worsens motor dysfunction. 7 Second-generation antipsychotics antagonize 5-HT 2A receptors in addition to D 2 receptors, but motor dysfunction might still be encountered. However, the relative amount of 5-HT 2 and D 2 antagonism is highly variable among second- generation antipsychotics. Those with very low D 2 affinity, such as clozapine and quetiapine, are currently the most commonly used medications to treat PDP. 7,10,11,16 Pharmacokinetics . Following administration of single oral doses of pimavanserin, brain imaging scans display dose-proportional pharmacokinetics. 12 Pimavanserin has one major active metabolite, AC-279. Mean plasma half-life of pimavanserin is 57 hours, and AC-279 is 200 hours. Pimavanserin's median time to peak concentration (T max ) is six hours (range 4–24), irrespective of dose. Median T max of the formation of AC-279 is also six hours. Mean maximum concentration (C max ) after a single, 100mg oral dose of pimavanserin in a fasted state is 57mg/mL, whereas mean area under the curve (AUC) under the same conditions is 3871h*ng/mL. 20 Pimavanserin tablets are 99.7-percent bioavailable. 21 Neither rate nor extent of pimavanserin exposure is significantly affected by concurrent ingestion of a high-fat meal, as C max decreases nine percent while AUC increases eight percent. 16,20,21 Average volume of distribution for pimavanserin following a single dose is 2,173L. 12 Pimavanserin is 95-percent protein bound in human plasma. Metabolism occurs primarily via cytochrome P450 enzyme (CYP) 3A4, the major contributor to formation of the active N-desmethylated metabolite, as well as CYP3A5. 12 To a lesser degree, pimavanserin is also metabolized via CYP2J2, CYP2D6, and other CYP and flavin- containing monooxygenase (FMO) enzymes. However, pimavanserin and metabolites do not inhibit or induce CYP enzymes to a clinically significant degree. Transporters do not appear to play a role in pimavanserin disposition. After an oral dose, 0.55 percent was excreted unchanged in the urine, while 1.53 percent was eliminated in feces. Pimavanserin pharmacokinetics are not significantly affected by weight, age, sex, or ethnicity. 12 Exposure in patients with mild-to-moderate renal impairment is similar to that of patients with normal renal function. Pharmacokinetic studies in patients with hepatic impairment or severe renal dysfunction are currently underway. 22 Clinical trials . Four RCTs have assessed pimavanserin in PDP, each showing that pimavanserin is safe and without negative impact on PD motor symptoms. 22–24 Preliminary data from two ongoing Phase IV, open-label, extension studies further support the relative safety of pimavanserin. 22 With regard to efficacy, only one of the four trials exhibited statistically significant improvement in the primary efficacy endpoint. 22–24 Among the earlier trials that did not demonstrate statistical significance, a Phase II study (ACP-103-006) was completed with results published that displayed a nonsignificant trend toward improvement in the primary outcome, along with significant improvement in a number of secondary efficacy measures. 23 Two other trials failed to show efficacy and are currently unpublished (ACP-103-012 and ACP-103-014), though data from these studies are available via the FDA and meeting abstracts. 22,25–27 Despite these early studies failing to show statistical significance, the FDA agreed to review the New Drug Application (NDA) submission of pimavanserin following the aforementioned single trial displaying significant improvement in PDP (ACP-103- 020). ACP-103-006, a Phase II study powered to detect effects on motor symptoms through the United Parkinson's Disease Rating Scale (UPDRS) Parts II and III, enrolled 60 subjects

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