Chemistry:Cariprazine

Short description: Atypical antipsychotic medicine

Cariprazine

Clinical data
Pronunciation	/kəˈrɪprəˌziːn/
Trade names	Vraylar, Reagila, Symvenu
Other names	RGH-188
AHFS/Drugs.com	Monograph
License data	US DailyMed: Cariprazine US FDA: Cariprazine
Pregnancy category	AU: D
Routes of administration	By mouth
Drug class	Atypical antipsychotic
ATC code	N05AX15 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	High
Protein binding	91–97%
Metabolism	Liver via CYP3A4 and to a lesser extent CYP2D6
Metabolites	desmethylcariprazine, didesmethylcariprazine
Elimination half-life	2–4 days for parent drug, and 1–3 weeks for active metabolites
Excretion	Urine (21%), bile
Identifiers
IUPAC name N'-[trans-4-[2-[4-(2,3-Dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea
CAS Number	839712-12-8
PubChem CID	11154555
IUPHAR/BPS	7671
DrugBank	DB06016
ChemSpider	25999972
UNII	F6RJL8B278
KEGG	D09997 as HCl: D09876
ChEBI	CHEBI:90933
ChEMBL	ChEMBL2028019
Chemical and physical data
Formula	C21H32Cl2N4O
Molar mass	427.41 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(CC2)c2cccc(Cl)c2Cl)CC1
InChI InChI=1S/C21H32Cl2N4O/c1-25(2)21(28)24-17-8-6-16(7-9-17)10-11-26-12-14-27(15-13-26)19-5-3-4-18(22)20(19)23/h3-5,16-17H,6-15H2,1-2H3,(H,24,28)/t16-,17- Y Key:KPWSJANDNDDRMB-QAQDUYKDSA-N Y

Cariprazine, sold under the brand names Vraylar, Reagila and Symvenu among others, is an atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D₃ and D₂ receptor partial agonist, with a preference for the D₃ receptor. Cariprazine is also a partial agonist at the serotonin 5-HT_1A receptor and acts as an antagonist at 5-HT_2B and 5-HT_2A receptors, with high selectivity for the D₃ receptor. It is taken by mouth.

Cariprazine was approved for medical use in the United States in September 2015. It was approved as a generic medication in 2022, but is covered by patents until 2029.

Medical uses

Cariprazine is used to treat patients with schizophrenia and manic, depressive, or mixed episodes associated with bipolar I disorder. In the United States it is approved for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression).

Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression. In Australia, the United Kingdom, and the European Union it is approved only for treating schizophrenia.

Side effects

Side effects may first appear several weeks after starting cariprazine. The most prevalent side effects for cariprazine include akathisia, and insomnia. Cariprazine does not appear to impact prolactin levels, and unlike many other antipsychotics, does not increase the QT interval on the electrocardiogram (ECG). In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo" but a second called the incidence of movement-related disorders "rather high".

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."

Because cariprazine and its active metabolites have long half-lives, many healthcare professionals monitor for adverse effects up to several weeks after starting cariprazine. A longer monitoring period is also indicated for dosage changes, whether they represent an increase or a decrease, because elimination may take several weeks.

Pharmacology

Pharmacodynamics

Site	Ki (nM)	IA (%)	Action
5-HT1A	2.6	~40%	Partial agonist
5-HT2A	18.8		Antagonist
5-HT2B	0.58		Antagonist
5-HT2C	134		Inverse agonist
5-HT7	111		Antagonist
α1A	155		Antagonist
D2L	0.49	~30%	Partial agonist
D2S	0.69	~30%	Partial agonist
D3	0.085	~70%	Partial agonist
H1	23.2		Antagonist
mACh	>1,000		Antagonist
The smaller the Ki value, the more strongly the drug binds to the site. IA=intrinsic activity.

Unlike many antipsychotics that are D₂ and 5-HT_2A receptor antagonists, cariprazine is a D₂ and D₃ partial agonist. It also has a higher affinity for D₃ receptors. The D₂ and D₃ receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine's high selectivity towards D₃ receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D₃ receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors. Cariprazine also acts on 5-HT_1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D₃ receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.

Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D₂/D₃ receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied. Dopamine D₂ and D₃ receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D₂/D₃ receptors, while striatal D₂/D₃ occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% [39]. In an open-label, fixed-dose, 2-week trial in eight males with schizophrenia, PET scans of dorsal striatal regions (caudate nucleus and putamen) and ventral striatum (nucleus accumbens) showed maximum occupancy (‡ 90%) at a 3-mg target dose of cariprazine following 14 d of treatment [40,41]. After 14 d of cariprazine 1.5 mg/d, receptor occupancy was 69% in the caudate nucleus, 69% in the nucleus accumbens, and 75% in the putamen".

Mechanism of cariprazine action as antagonist or agonist.

Cariprazine, as well as other third generation antipsychotics, possesses a lower chance of exacerbating extrapyramidal symptoms. However the ability to induce akathasia remains relatively high. This may be mediated through a lack of anticholinergic effects (as agents of this class are sometimes used to treat akathisia), as well as a lack of a balanced dopaminergic(D₂)/serotonergic(5-HT_2A) ratio (compared to the second generation antipsychotics serving a more nuanced profile in this regard). Moreover, partial agonists, through their limited response triggering, ironically often have the tendency to occupy near all targeted receptors at relatively low dosages of the drug. An extreme example is aripiprazole with an average occupancy of 70% (D₂) at a 2 mg dose, well below its usual antipsychotic dosage (the often cited threshold of occupancy for an antipsychotic effect is 70%). This could be another reason for akathasia from partial agonists.

Pharmacokinetics

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic. In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).

Cariprazine is metabolized primarily by the cytochrome P450 3A4 isoenzyme (CYP3A4), with some minor metabolism by CYP2D6. Cariprazine does not induce the production of CYP3A4 or CYP1A2 in the liver, and weakly, competitively inhibits CYP2D6 and CYP3A4.

Research

Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015.

Cariprazine is also potentially useful as an add-on therapy in major depressive disorder. It is being developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the US, Canada, Japan, Taiwan and certain Latin American countries (including Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela). In February 2022, AbbVie requested approval by the US Food and Drug Administration (FDA) for adjunctive treatment for major depressive disorder. Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.

Chemistry

Cariprazine is a 2,3-dichlorophenylpiperazine class drug and is chemically related to aripiprazole.