2.

DRUG PROFILE
Name : Pimavanserin

Description : Pimavanserin (ACP-103), marketed under the trade name Nuplazid, is a

drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin
receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or
activity at 5-HT2B or dopamine receptors. As of September 3, 2009, pimavanserin has not met
expectations for Phase III clinical trials for the treatment of Parkinson's disease psychosis, and is
in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic
medication. It is expected to improve the effectiveness and side effect profile of antipsychotics.
The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive
pimavanserin to risperidone and haloperidol were published in November 2012 and the results
showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of
risperidone and improve the tolerability of haloperidol treatment by reducing the incidence of
extrapyramidal symptoms. On September 2, 2014, the United States Food and Drug
administration granted Breakthrough Therapy status to Acadia's New Drug Application for
pimavanserin.

Structure :

Molecular Weight : 427.564

Chemical Formula : C25H34FN3O2

IUPAC Name : 1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-

methylpropoxy)phenyl]methyl}urea
Indication : Investigated for use/treatment in neurologic disorders, parkinson's disease,
psychosis, schizophrenia and schizoaffective disorders, and sleep disorders.

Mechanism of action : ACP-103 reduces haloperidol-induced akathisia, a debilitating

extrapyramidal side effect (EPS), in patients with schizophrenia. ACP-103 is a 5-HT2A inverse
agonist, to reduce the side effects associated with antipsychotic drug treatment with haloperidol.
ACP-103 reduced both the motor disturbances and hyperprolactinemia, a condition of elevated
prolactin secretion, caused by haloperidol treatment.

Volume of distribution : 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.

Metabolism : Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5 and to a

lesser extent by CYP2J2, CYP2D6, and various other CYP and FMO enzymes. CYP3A4 is the
major enzyme responsible for the formation of its major active metabolite (AC-279).

Route of Elimination : Pimavanserin is not recommended to be used in patients with severe

renal impairment (CrCl < 30 mL/min). ... ➢ The elimination half-life of pimavanserin and its

active metabolite, AC-279 are about 57 and 200 hours, respectively.

Half life : Pimavanserin and its major active N-desmethylated metabolite AC-279 have
demonstrated a time to maximum plasma concentration of six hours (range, four to 24 hours)
with mean plasma half-lives of approximately 57 hours for pimavanserin and 200 hours for AC-
279.

Toxicity : Pimavanserin may increase the central nervous system depressant (CNS
depressant) activities of Atropine. The risk or severity of adverse effects can be increased when
Pimavanserin is combined with Azaperone. The risk or severity of adverse effects can be
increased when Pimavanserin is combined with AZD-3043.

Affected organisms : Humans and other mammals