Pharmacokinetics, Tolerability, and Safety of ACP‐103 Following Single or Multiple Oral Dose Administration in Healthy Volunteers

Vanover, Kimberly E.; Robbins-Weilert, Doris K.; Wilbraham, Darren; Mant, Timothy; Kammen, Daniël P. van; Davis, Robert E.; Weiner, David M.

doi:10.1177/0091270007299431

Cited by 34 publications

(51 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Initial clinical studies in normal healthy volunteers showed that pimavanserin was well tolerated in humans both when given acutely and subchronically [38]. Nausea and vomiting were considered to be dose-limiting following 14 days of once daily oral dosing at 150 mg; 100 mg QD of pimavanserin given over the same period was therefore estimated to be the maximum tolerated dose.…”

Section: Clinical Studies With Pimavanserinmentioning

confidence: 99%

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

et al. 2014

View full text Add to dashboard Cite

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

show abstract

Section: Clinical Studies With Pimavanserinmentioning

confidence: 99%

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Indeed, newer highly selective 5-HT 2A receptor antagonists, like M100907 (volinanserin), ACP-103 (primavanserin), and SR46349B (eplivanserin), are currently in clinical trials as novel therapeutics to treat insomnia [68] and there are no reports in literature describing effects on hypertension, inflammation, or other cardiovascular processes. One report, however, examining the physiological and pharmacokinetics of ACP-103 in a small study comprised of normal human subjects has been published that concluded that there were no significant changes in vital signs or ECG associated with treatment for up to fourteen days [69]. …”

mentioning

confidence: 99%

Serotonin 5- Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases

Nichols

2009

Cardiovascular Psychiatry and Neurology

View full text Add to dashboard Cite

There are high levels of comorbidity between neuropsychiatric and cardiovascular disorders. A key molecule central to both cognitive and cardiovascular function is the molecule serotonin. In the brain, serotonin modulates neuronal activity and is actively involved in mediating many cognitive functions and behaviors. In the periphery, serotonin is involved in vasoconstriction, inflammation, and cell growth, among other processes. It is hypothesized that one component of the serotonin system, the 5-HT2A receptor, is a common and contributing factor underlying aspects of the comorbidity between neuropsychiatric and cardiovascular disorders. Within the brain this receptor participates in processes such as cognition and working memory, been implicated in effective disorders such as schizophrenia, and mediate the primary effects of hallucinogenic drugs. In the periphery, 5-HT2A receptors have been linked to vasoconstriction and hypertension, and to inflammatory processes that can lead to atherosclerosis.

show abstract

“…Preliminary studies assessing adverse effects and bioavailability in healthy controls suggested minimal issues with tolerability and long half life of pimavanserin 20-50 mg without interference from food [Vanover et al 2007a[Vanover et al , 2007b. The high affinity of pimavanserin for 5HT2A receptors [Nordstrom et al 2008] stimulated great interest in its potential for treating PDP.…”

Section: Clinical Trials Of Pimavanserin In Pdpmentioning

confidence: 99%

Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis

Sarva

Henchcliffe

2016

Ther Adv Neurol Disord

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with both motor and nonmotor symptoms (NMS), leading to significant morbidity and caregiver burden. Psychosis is common but is under recognized by physicians. When present, it increases the patient’s risk of hospitalization and nursing home placement and caregiver burden. Although the atypical antipsychotic agent, clozapine, has been considered the gold standard treatment, severe agranulocytosis in 0.38% of patients and more commonly milder leukopenia, resulting in frequent blood testing, limit its use. Pimavanserin, a 5HT2A receptor inverse agonist, has been shown to reduce psychosis in PD without worsening motor symptoms. It is therefore a welcome therapeutic option for this devastating NMS.

show abstract

Pharmacokinetics, Tolerability, and Safety of ACP‐103 Following Single or Multiple Oral Dose Administration in Healthy Volunteers

Cited by 34 publications

References 10 publications

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Serotonin 5- Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases

Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis

Contact Info

Product

Resources

About