Chemistry:Cariprazine

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Short description: Atypical antipsychotic medicine
Cariprazine
Cariprazine.svg
Cariprazine ball-and-stick model.png
Clinical data
Pronunciation/kəˈrɪprəˌziːn/
Trade namesVraylar, Reagila, Symvenu
Other namesRGH-188
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H32Cl2N4O
Molar mass427.41 g·mol−1
3D model (JSmol)

Cariprazine, sold under the brand names Vraylar, Reagila and Symvenu among others, is an atypical antipsychotic originated by Gedeon Richter,[7] which is used in the treatment of schizophrenia, bipolar mania,[8] bipolar depression,[9] and major depressive disorder.[5] 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-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor.[10] It is taken by mouth.[5]

Cariprazine was approved for medical use in the United States in September 2015.[11] It was approved as a generic medication in 2022,[12] but is covered by patents until 2029.[13]

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).[14][5][15]

Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression.[16][17] In Australia, the United Kingdom, and the European Union it is approved only for treating schizophrenia.[4][6][18]

Side effects

Side effects may first appear several weeks after starting cariprazine.[5] 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"[19] but a second called the incidence of movement-related disorders "rather high".[20][21]

Regarding these side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."[5]

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.[22]

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-HT2A 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.[23] 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.[24] 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).[24][25] 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.[24] 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.[19] 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.[25] 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".[19]

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].[26][27][28] 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.[29][30]

Pharmacokinetics

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.[31] In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).[21]

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.[14]

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.[32][31]

Cariprazine is also potentially useful as an add-on therapy in major depressive disorder.[33] 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.[34] Approval was granted by the FDA in December 2022 for cariprazine to be used as an adjunctive treatment for major depressive disorder.[35]

Chemistry

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

References

  1. ↑ 1.0 1.1 "AusPAR: Cariprazine hydrochloride". 21 June 2022. https://www.tga.gov.au/resources/auspar/auspar-cariprazine-hydrochloride. 
  2. ↑ "Vraylar Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=101585. 
  3. ↑ "Summary Basis of Decision - Vraylar". 26 August 2022. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00601&lang=en. 
  4. ↑ 4.0 4.1 "Reagila 1.5 mg hard capsules - Summary of Product Characteristics (SmPC)". 9 August 2018. https://www.medicines.org.uk/emc/product/9401/smpc. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Vraylar- cariprazine capsule, gelatin coated Vraylar- cariprazine kit". 18 May 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4b5f7c65-aa2d-452a-b3db-bc85c06ff12f. 
  6. ↑ 6.0 6.1 "Reagila EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/reagila. 
  7. ↑ "Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety". Advances in Therapy 38 (7): 3652–3673. July 2021. doi:10.1007/s12325-021-01797-5. PMID 34091867. 
  8. ↑ "Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors". Bioorganic & Medicinal Chemistry Letters 22 (10): 3437–3440. May 2012. doi:10.1016/j.bmcl.2012.03.104. PMID 22537450. 
  9. ↑ "Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study". The American Journal of Psychiatry 176 (6): 439–448. June 2019. doi:10.1176/appi.ajp.2018.18070824. PMID 30845817. 
  10. ↑ "Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile". The Journal of Pharmacology and Experimental Therapeutics 333 (1): 328–340. April 2010. doi:10.1124/jpet.109.160432. PMID 20093397. 
  11. ↑ "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.
  12. ↑ "2022 First Generic Drug Approvals". 3 March 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals. 
  13. ↑ "Generic Vraylar Availability". 9 March 2023. https://www.drugs.com/availability/generic-vraylar.html. 
  14. ↑ 14.0 14.1 "Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability". Expert Opinion on Drug Metabolism & Toxicology 9 (2): 193–206. February 2013. doi:10.1517/17425255.2013.759211. PMID 23320989. 
  15. ↑ "Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials". Frontiers in Psychiatry 12: 769897. 2021. doi:10.3389/fpsyt.2021.769897. PMID 34970166. 
  16. ↑ "Efficacy of cariprazine in bipolar I depression across patient characteristics: a post hoc analysis of pooled randomized, placebo-controlled studies". International Clinical Psychopharmacology 36 (2): 76–83. March 2021. doi:10.1097/YIC.0000000000000344. PMID 33230026. 
  17. ↑ "Cariprazine as a Treatment Option for Depressive Episodes Associated with Bipolar 1 Disorder in Adults: An Evidence-Based Review of Recent Data". Drug Design, Development and Therapy 15: 2005–2012. 2021. doi:10.2147/DDDT.S240860. PMID 34012253. 
  18. ↑ "Cariprazine hydrochloride for schizophrenia". Australian Prescriber 44 (5): 170–171. October 2021. doi:10.18773/austprescr.2021.047. PMID 34728883. 
  19. ↑ 19.0 19.1 19.2 "Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy". Advances in Therapy 30 (2): 114–126. February 2013. doi:10.1007/s12325-013-0006-7. PMID 23361833. 
  20. ↑ "Cariprazine, a new, orally active dopamine D2/3 receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression". Expert Review of Neurotherapeutics 13 (11): 1141–1159. November 2013. doi:10.1586/14737175.2013.853448. PMID 24175719. 
  21. ↑ 21.0 21.1 "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties". Psychopharmacology 216 (4): 451–473. August 2011. doi:10.1007/s00213-011-2247-y. PMID 21394633. 
  22. ↑ "Cariprazine". Prescriber's Guide: Stahl's Essential Psychopharmacology (7th ed.). Cambridge: Cambridge University Press. 2020. pp. 137–146. doi:10.1017/9781108921275.024. ISBN 978-1-108-92601-0. https://www.cambridge.org/core/books/prescribers-guide/cariprazine/F5A7E531908E0A04808881D91C06A124. Retrieved 11 October 2022. 
  23. ↑ "Schizophrenia: more dopamine, more D2 receptors". Proceedings of the National Academy of Sciences of the United States of America 97 (14): 7673–7675. July 2000. doi:10.1073/pnas.97.14.7673. PMID 10884398. Bibcode: 2000PNAS...97.7673S. 
  24. ↑ 24.0 24.1 24.2 "Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents". Neurochemistry International 59 (6): 925–935. November 2011. doi:10.1016/j.neuint.2011.07.002. PMID 21767587. 
  25. ↑ 25.0 25.1 "Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography". Psychopharmacology 218 (3): 579–587. December 2011. doi:10.1007/s00213-011-2343-z. PMID 21625907. 
  26. ↑ "Pharmacological management of antipsychotic-induced akathisia: an update and treatment algorithm.". BJPsych Advances 21 (5): 342–344. September 2015. doi:10.1192/apt.bp.114.013797. 
  27. ↑ "Cariprazine and akathisia, restlessness, and extrapyramidal symptoms in patients with bipolar depression". Journal of Affective Disorders 288: 191–198. June 2021. doi:10.1016/j.jad.2021.03.076. PMID 33915374. 
  28. ↑ "Risperidone". Pharmacotherapy 14 (3): 253–65. 1994. doi:10.1002/j.1875-9114.1994.tb02819.x. PMID 7524043. 
  29. ↑ "Full agonists, partial agonists and inverse agonists | Deranged Physiology". https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacodynamics/Chapter%20417/full-agonists-partial-agonists-and-inverse-agonists. 
  30. ↑ "Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride". Neuropsychopharmacology 27 (2): 248–259. August 2002. doi:10.1016/S0893-133X(02)00304-4. PMID 12093598. 
  31. ↑ 31.0 31.1 "Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression". Current Opinion in Investigational Drugs 11 (7): 823–832. July 2010. PMID 20571978. 
  32. ↑ "An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression". The American Journal of Psychiatry 173 (3): 271–281. March 2016. doi:10.1176/appi.ajp.2015.15020164. PMID 26541814. 
  33. ↑ "Safety and Efficacy of Cariprazine As Adjunctive Therapy In Major Depressive Disorder". U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT00854100. 
  34. ↑ "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.
  35. ↑ "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.



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