Cariprazine

Structural formula
General
Surname	Cariprazine
other names	N '- [ trans -4- [2- [4- (2,3-dichlorophenyl) -1-piperazinyl] ethyl] cyclohexyl] - N , N -dimethylurea
Molecular formula	C 21 H 32 Cl 2 N 4 O
External identifiers / databases
CAS number 839712-12-8 1083076-69-0 (hydrochloride) PubChem 11154555 ChemSpider 25999972 DrugBank DB06016 Wikidata Q2938837
Drug information
ATC code	N05 AX15
properties
Molar mass	427.41 g mol −1
solubility	practically insoluble in water
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cariprazine is an antipsychotic agent from the group of atypical neuroleptics used to treat schizophrenia in adults.

The active ingredient acts as a D3 selective D2 / D3 receptor partial agonist and thus differs from all other antipsychotics .

In the EU, the European Medicines Agency (EMA) recommended approval of the substance in the form of hard capsules in July 2017. The market launch in Germany took place in April 2018. In October 2019, Cariprazin was the first antipsychotic to receive the Galenus von Pergamon Prize in the “Specialist Care” category. This was preceded by the first recommendation of an additional benefit for an antipsychotic by the Institute for Quality and Efficiency in Health Care ( IQWiG ) to the Federal Joint Committee ( G-BA ). In addition to the recommendation of the IQWIG, this attested an additional benefit compared to the study comparator medication ( risperidone ) in the long-term treatment of patients with predominantly negative symptoms of schizophrenia.

Cariprazine was developed as RGH-188 by the Hungarian pharmaceutical company Gedeon Richter based in Budapest , the active ingredient is marketed in Germany by Recordati Pharma GmbH, Ulm.

Clinical information

application areas

Cariprazine is used to treat schizophrenia in adult patients.

effectiveness

In addition to good antipsychotic effects, the receptor binding profile of cariprazine also has a beneficial effect on the treatment of schizophrenia-related negative symptoms and the side effect profile.

The study program demonstrated its effectiveness in the acute phase (6 weeks), in long-term therapy (72 weeks) and in patients with predominantly negative symptoms. The side effect and tolerability profile can be classified as favorable on the basis of all studies.

unwanted effects

With regard to the cardiovascular, metabolic and sedative side effects as well as the hyperprolactinemia , cariprazine is inconspicuous. The most common possible undesirable effects include extrapyramidal disorders such as akathisia and parkinsonism , with these side effects usually being mild to moderate.

Studies

Overall, the data from 5 clinical efficacy studies show that cariprazine improves a wide range of schizophrenia symptoms (positive and negative symptoms) at all stages of the disease and has a similar safety profile to other approved antipsychotics. Nevertheless, cariprazine is outstanding in the treatment of predominantly negative symptoms in schizophrenia.

• Based on the data from three double-blind short-term studies, the effectiveness of cariprazine in the treatment of acute exacerbations of the positive and negative symptoms in schizophrenia was confirmed. The PANSS value (Positive and Negative Syndrome Scale maximum 210 points) improved with cariprazine by up to 25.9 points. This improvement was also statistically significant compared to the placebo arm (improvement of up to 16.0). The effectiveness in acute therapy can thus be classified as comparable to other atypicals.

• A sustaining effect study demonstrated the long-term effectiveness of cariprazine in schizophrenia. By the end of the study after 72 weeks, 21.6 percent of patients treated with cariprazine had a relapse, compared with 49 percent with placebo ( statistically significant difference).

• A study on a special patient subpopulation with predominantly negative symptoms in schizophrenia showed a statistically significantly better effectiveness compared to risperidone. For the first time, two atypicals were compared with each other in a direct comparison. This study was the basis on which the G-BA had attested an additional benefit for cariprazine.

Pharmacological properties

Mechanism of action

The mechanism of action of cariprazine is not yet fully understood. The therapeutic effect of cariprazine is possibly due to a combination of a partial agonistic activity on the dopamine D3, dopamine D2 and serotonin 5-HT1A receptors as well as an antagonistic activity on the serotonin 5-HT2B , 5-HT2A and mediates histamine H1 receptors .

In addition, cariprazine has a low affinity for the serotonin 5-HT2C receptors and the α1-adrenergic receptors and has no significant affinity for cholinergic muscarinic receptors (IC50> 1,000 nM). The two main active metabolites, desmethylcariprazine and didesmethylcariprazine, have a similar receptor binding and functional activity profile in vitro as the parent substance .

Pharmacodynamic effects

In vitro, cariprazine exhibits partial agonistic activity and has a high affinity for both the D3 and D2 receptors. Preclinical in vivo studies have shown that cariprazine occupies D3 receptors to a similar extent as D2 receptors at pharmacologically effective doses.

In schizophrenic patients who took cariprazine within the therapeutic dose range for 15 days, cariprazine showed dose-dependent occupancy of D3 and D2 receptors in the brain (with preferential occupation in regions with higher D3 expression).

Absorption and distribution in the body

The absolute bioavailability of cariprazine is not yet known. The active ingredient is well absorbed after oral administration. After multiple doses, peak plasma levels of cariprazine and the major active metabolites are generally reached 3–8 hours after ingestion.

Administration of a single dose of cariprazine 1.5 mg with a high-fat meal (900–1,000 calories) had no relevant effects on the Cmax or AUC of cariprazine (postprandial increase in AUC 0– ∞ by 12% and decrease in Cmax by <5 %, in each case compared to the fasted state). The effects of a meal on exposure to the metabolites DCAR and DDCAR were also minimal. Cariprazine can be taken with or without a meal. [14]

Trade names

• Reagila (EU), Vraylar (USA)

See also

• List of antipsychotics

Web links

• Institute for Quality and Efficiency in Health Care (IQWiG). Cariprazine (schizophrenia). Dossier assessment A18-25 . Version 1.0 dated July 12, 2018
• G-BA decision of October 4, 2018: Indication of a minor additional benefit compared to risperidone
• FDA public assessment report on Vraylar

Individual evidence

1. ↑ External identifiers or database links for cariprazine hydrochloride : CAS number: 1083076-69-0, EC number: 805-320-1, ECHA InfoCard: 100.232.087 , PubChem : 25096873 , ChemSpider : 28504138 , DrugBank : DBSALT001260 , Wikidata : Q27162922 .
2. ↑ entry to Cariprazin in the Hazardous Substances Data Bank , accessed on 29 July 2017th
3. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
4. ↑ Leslie Citrome: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. In: Expert Opinion on Drug Metabolism & Toxicology. 9, 2012, p. 193, doi: 10.1517 / 17425255.2013.759211
5. ↑ ^{a b} EMA recommendation, accessed on January 27, 2020.
6. ↑ Doctors newspaper, October 20, 2019. Awarded the Galenus Medal five times. Accessed January 27, 2020
7. ↑ G-BA benefit assessment of cariprazine . Retrieved January 27, 2020.
8. ↑ Yellow list of specialist information . Retrieved January 27, 2020
9. ↑ ^{a b} Durgam S et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophrenia Research 2014; 152: 450-457. doi: 10.1016 / j.schres.2013.11.041
10. ↑ ^{a b} Durgam S et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. Journal of Clinical Psychiatry 2015; 76: e1574-1582. doi: 10.4088 / JCP.15m09997
11. ↑ ^{a b} Kane JM et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. Journal of Clinical Psychopharmacology 2015; 35: 367-373. doi: 10.1097 / JCP.0000000000000346
12. ↑ ^{a b} Durgam S et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. Schizophrenia Research 2016; 176: 264-271. doi: 10.1016 / j.schres.2016.06.030
13. ↑ ^{a b} 12. Németh G et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomized, double-blind, controlled trial. Lancet 2017; 389: 1103-1113. doi: 10.1016 / S0140-6736 (17) 30060-0
14. ↑ Yellow list. Launch of Reagila ^® . Accessed January 27, 2020.
15. ↑ Yellow list: Cariprazine . Accessed January 27, 2020.
16. ↑ Kiss B et al. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3 / D2 dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. Journal of Pharmacology and Experimental Therapeutics 2010; 333: 328-340. doi: 10.1124 / jpet.109.160432
17. ↑ Girgis RR et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3 / D2 receptor ligand [11C] - (+) - PHNO. Psychopharmacology 2016; 233: 3503-3512. doi: 10.1007 / s00213-016-4382-y

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