2013-03-13

Cariprazine (RGH-188)

Cariprazine (RGH-188) is an antipsychotic drug by Gedeon Richter. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.[1] Positive Phase III study results were published for schizophrenia and mania early 2012, while Phase II studies in bipolar disorder I, and for bipolar depression are in progress. [2] Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder [3]

Forest Laboratories obtained a license on development and exclusive commercial rights in the US in 2004.

Treatment mechanisms

Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia. [4] 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. [5] 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 syndrome) as drugs that act on dorsal striatum dopamine receptors. [6] 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). [7][8] In the same studies, cariprazine has been noted to increase procognitive 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. [9] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.
Pharmacodynamics and pharmacokinetics

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. [10] It is highly potent at D3/D2 sites, and has a low potency at 5-HT2C sites. Cariprazine shows a ten-fold selectivity selectivity for D3 receptors (pKd~10) over D2 receptors (pKd~9). It has similar efficacies at both D2 and D3 sites. [11] In monkey studies, the administration of increasing does 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 (1.0 μg/kg), receptors were 5 % occupied. [12] Cariprazine has a high oral bioavailability and can cross the blood brain barrier easily in humans because it it lipophilic. [13] In rats, the oral bioavailability was 52 % (with a dose of 1 mg/kg). [14]

In phase II studies of cariprazine on schizophrenia, 732 patients were randomly placed into 1 of 5 treatment groups (1.5 mg/day cariprazine, 3.0 mg/day cariprazine, and 4.5 mg/day cariprazine, 4mg/day risperidone, and placebo). The patients receiving risperidone or cariprazine had fewer symptoms than those on placebos. [15]
Side effects

The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. In Phase III trial for schizophrenia, 66.7 % of patients experienced these side effects, as well as other issues such as metabolic problems, extrapyramidal syndrome (EPS) side effects, and sedation. This suggests that cariprazine might not make it past Phase III testing for schizophrenia because its tolerability is lower those of its competitors. [16] Other medications cause many motor defects and EPS side effects, which are major problems for patients who did not have motor issues before taking the medicine. [17] These motor issues are due to the fact that dopamine acts on the motor pathway as well as the reward pathway, and many antipsychotics agonize the dopamine pathway, causing excessive motor movement as well as the intended effects.

These side effects are considerably lower in the phase III trials for bipolar disorder 1 (for unknown reasons). [18]


References

  1. Kiss B; Horváth A; Némethy Z; Schmidt E; Laszlovszky I; Bugovics G; Fazekas K; Hornok K et al. (2010). "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. doi:10.1124/jpet.109.160432. PMID 20093397.
  2. Gründer G (2010). "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. PMID 20571978.
  3. Clinical trial : Safety and Efficacy of Caripazine As Adjunctive Therapy In Major Depressive Disorder
  4. Gyertyan, I., B. Kiss, et al. (2011). "Cariprazine (RGH-188), a potent D-3/D-2 dopamine receptor partial agonist, binds to dopamine D-3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents." Neurochemistry International 59(6): 925-935.
  5. Seeman P; Kapur S. (2000). “Schizophrenia: More Dopamine, more D-2 receptors. Proceedings of the National Academy of the Sciences of the United States of America. 97 (14): 7673-7675.
  6. Gyertyan, I., B. Kiss, et al. (2011). "Cariprazine (RGH-188), a potent D-3/D-2 dopamine receptor partial agonist, binds to dopamine D-3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents." Neurochemistry International 59(6): 925-935.
  7. Gyertyan, I., B. Kiss, et al. (2011). "Cariprazine (RGH-188), a potent D-3/D-2 dopamine receptor partial agonist, binds to dopamine D-3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents." Neurochemistry International 59(6): 925-935.
  8. Seneca, N., S. J. Finnema, et al. (2011). "Occupancy of dopamine D-2 and D-3 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.
  9.  Gyertyan, I., B. Kiss, et al. (2011). "Cariprazine (RGH-188), a potent D-3/D-2 dopamine receptor partial agonist, binds to dopamine D-3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents." Neurochemistry International 59(6): 925-935.
  10. Agai-Csongor, E., G. Domany, et al. (2012). "Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D-3/D-2 receptors." Bioorganic & Medicinal Chemistry Letters 22(10): 3437-3440.
  11. Albert, Jeffrey S. (2012). Targets and Emerging Therapies for Schizophrenia. New York, Wiley.
  12. Seneca, N., S. J. Finnema, et al. (2011). "Occupancy of dopamine D-2 and D-3 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.
  13. Gründer G (2010). "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. PMID 20571978.
  14. Newman-Tancredi, A. and M. S. Kleven (2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D-2 and serotonin 5-HT1A receptor properties." Psychopharmacology 216(4): 451-473.
  15. Albert, Jeffrey S. (2012). Targets and Emerging Therapies for Schizophrenia. New York, Wiley.
  16. APA 2012: Cariprazine Fails to Offer a Therapeutic Breakthrough (2012). Datamonitor Research Store. Retrieved from <http://www.datamonitor.com/store/News/apa_2012_cariprazine_fails_to_offer_a_therapeutic_breakthrough?productid=82F68FAC-1836-45D1-802A-98CAF3269947>
  17. Newman-Tancredi, A. and M. S. Kleven (2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D-2 and serotonin 5-HT1A receptor properties." Psychopharmacology 216(4): 451-473.
  18. APA 2012: Cariprazine Fails to Offer a Therapeutic Breakthrough (2012). Datamonitor Research Store. Retrieved from <http://www.datamonitor.com/store/News/apa_2012_cariprazine_fails_to_offer_a_therapeutic_breakthrough?productid=82F68FAC-1836-45D1-802A-98CAF3269947>


Source: wikipedia.org