Cariprazine

Source: Wikipedia, the free encyclopedia.

Cariprazine
Clinical data
Pronunciation/kəˈrɪprəˌziːn/
Trade namesVraylar, Reagila, Symvenu
Other namesRGH-188
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityHigh
Protein binding91–97%
MetabolismLiver via CYP3A4 and to a lesser extent CYP2D6
Metabolitesdesmethylcariprazine, didesmethylcariprazine
Elimination half-life2–4 days for parent drug, and 1–3 weeks for active metabolites
ExcretionUrine (21%), bile
Identifiers
  • N'-[trans-4-[2-[4-(2,3-Dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea
JSmol)
  • CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(CC2)c2cccc(Cl)c2Cl)CC1
  • 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- checkY
  • Key:KPWSJANDNDDRMB-QAQDUYKDSA-N checkY

Cariprazine, sold under the brand names Vraylar, Reagila and Symvenu among others, is an

by mouth.[6]

Cariprazine was approved for medical use in the United States in September 2015.

generic medication in 2022,[13] but is covered by patents until 2029.[14]

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).[15][6][16]

Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression.[17][18] In Australia, the United Kingdom, and the European Union it is approved only for treating schizophrenia.[5][7][19]

Side effects

Side effects may first appear several weeks after starting cariprazine.[6] 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"[20] but a second called the incidence of movement-related disorders "rather high".[21][22]

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."[6]

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.[23]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Cariprazine[24][15][25][26]
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
mAChTooltip Muscarinic acetylcholine receptor >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-HT2A

dorsal striatum dopamine receptors.[28] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[28][29] 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.[28]
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.[20] 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.[29] 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".[20]

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-HT2A) ratio (compared to the second generation antipsychotics serving a more nuanced profile in this regard)[clarify].[30][31][32] 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.[33][34]

Pharmacokinetics

Cariprazine has high oral

blood brain barrier easily in humans because it is lipophilic.[35] In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).[22]

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.[15]

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.[36][35]

Cariprazine is also potentially useful as an

add-on therapy in major depressive disorder.[37] 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.[38] Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.[39]

Chemistry

Cariprazine is a

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

References

  1. ^ a b "AusPAR: Cariprazine hydrochloride". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 18 April 2023.
  2. FDA
    . Retrieved 22 October 2023.
  3. ^ "Vraylar Product information". Health Canada. 25 April 2012. Archived from the original on 29 June 2022. Retrieved 29 June 2022.
  4. ^ "Summary Basis of Decision - Vraylar". Health Canada. 26 August 2022. Archived from the original on 29 September 2022. Retrieved 29 September 2022.
  5. ^ a b "Reagila 1.5 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 9 August 2018. Archived from the original on 21 October 2020. Retrieved 20 October 2020.
  6. ^ a b c d e f "Vraylar- cariprazine capsule, gelatin coated Vraylar- cariprazine kit". DailyMed. 18 May 2019. Archived from the original on 24 October 2020. Retrieved 20 October 2020.
  7. ^ a b "Reagila EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 24 October 2020. Retrieved 20 October 2020.
  8. PMID 34091867
    .
  9. PMID 22537450
    .
  10. PMID 30845817
    .
  11. S2CID 42933132
    .
  12. ^ "FDA approves new drug to treat schizophrenia and bipolar disorder" (Press release). U.S. Food and Drug Administration. 17 September 2015. Archived from the original on 26 January 2018. Retrieved 16 December 2019.
  13. ^ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  14. ^ "Generic Vraylar Availability". Drugs.com. 9 March 2023. Retrieved 26 March 2023.
  15. ^
    S2CID 36750662
    .
  16. PMID 34970166
    .
  17. PMID 33230026
    .
  18. PMID 34012253
    .
  19. PMID 34728883
    .
  20. ^
    PMID 23361833
    .
  21. S2CID 23557344
    .
  22. ^
    S2CID 5835943
    .
  23. ISBN 978-1-108-92601-0
    . Retrieved 11 October 2022.
  24. ^ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 22 May 2021. Retrieved 14 August 2017.
  25. S2CID 53096758
    .
  26. PMID 35145438
    .
  27. PMID 10884398
    .
  28. ^
    S2CID 140205658
    .
  29. ^
    PMID 21625907
    .
  30. S2CID 146670706
    .
  31. S2CID 233462432
    .
  32. PMID 7524043
    .
  33. ^ "Full agonists, partial agonists and inverse agonists | Deranged Physiology".
  34. S2CID 26101524
    .
  35. ^
    PMID 20571978
    .
  36. PMID 26541814
    .
  37. ^ "Safety and Efficacy of Cariprazine As Adjunctive Therapy In Major Depressive Disorder". ClinicalTrials.gov. U.S. National Library of Medicine. Archived from the original on 6 December 2018. Retrieved 6 December 2018.
  38. ^ "AbbVie Submits Supplemental New Drug Application to U.S. FDA for cariprazine (major depressive disorder) for the Adjunctive Treatment of Major Depressive Disorder". AbbVie (Press release). Retrieved 11 October 2022.
  39. ^ "U.S. FDA Approves Vraylar (cariprazine) as an Adjunctive Treatment for Major Depressive Disorder" (Press release). AbbVie. 16 December 2022. Retrieved 3 January 2023 – via PR Newswire.