Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine

Abstract

Introduction:# 

Cariprazine, a dopamine D₃-preferring D₃/D₂ receptor partial agonist and serotonin 5-HT_1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.

Methods

In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR.

Results

Similar to cariprazine, both metabolites showed high affinity for human D₃, D_2L, 5-HT_1A, 5-HT_2A, and 5-HT_2B receptors, albeit with higher selectivity than cariprazine for D₃ versus D₂ receptors. In [³⁵S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D₂ and D₃ receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D₂ and D₃ receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT_1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT_2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D₃ receptor occupancy in rat brain; however, cariprazine was more potent for D₂ receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D₂ receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.

Conclusion

Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

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Keywords:

• dopamine
• serotonin
• schizophrenia
• bipolar disorder
• desmethyl-cariprazine
• didesmethyl-cariprazine

Acknowledgments

The authors would like to thank Dr Éva Schmidt and Dr Anikó Gere of Gedeon Richter Plc (Budapest, Hungary) for conducting the receptor binding experiments, Dr Sándor Kolok and Dr Zoltán Kapui of Gedeon Richter Plc for conducting the functional experiments, Dr Judit Laszy of Gedeon Richter Plc for conducting the behavioral experiments, Dr Mónika Vastag of Gedeon Richter Plc for conducting the in vitro metabolism experiments, Dr Margit Kapás of Gedeon Richter Plc for conducting the pharmacokinetic experiments, Éva Ágai Csongor and Dr György Domány of Gedeon Richter Plc for synthesizing cariprazine and metabolites, Dr Christer Halldin and Dr Balázs Gulyás of Karolinska Institute (Stockholm, Sweden) for managing the positron emission tomography study, and Dr Nika Adham of Allergan (Madison, NJ, USA) and Dr Zsolt Szombathelyi of Gedeon Richter Plc (Ridgewood, NJ, USA) for their critical review and edits of the manuscript.

The authors express their sincere thanks for the expert technical assistance from all of our colleagues from Gedeon Richter Plc actively participating in the presented experiments.

Writing and editorial assistance was provided to the authors by Jennifer Fetting, PhD, and Katharine Fang, PhD, of Prescott Medical Communications Group (Chicago, IL, USA), a contractor of Allergan. These studies were sponsored by Gedeon Richter Plc. This manuscript was supported by funding from Allergan and Gedeon Richter Plc.

István Gyertyán’s present affiliation is Semmelweis University, Institute of Pharmacology and Pharmacotherapy, NAP Cognitive Translational Behavioral Pharmacology Group, Budapest, Hungary.

Abbreviation list

Cariprazine (RGH-188), trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimethylureahydrochloride; 5-HT, serotonin; hD₂, human recombinant dopamine D₂ receptor; hD₃, human recombinant dopamine D₃ receptor; h5-HT_1A, human recombinant serotonin 5-HT_1A receptor; h5-HT_2B, human recombinant serotonin 5-HT_2B receptor; DCAR, desmethyl-cariprazine; DDCAR, didesmethyl-cariprazine; DOPA, 3,4-dihydroxyphenylalanine; DOPAC, 3,4-dihydroxyphenyl acetic acid; HVA, homovanillic acid; 5-HIAA, 5-hydroxy-indolyl acetic acid; CHO, Chinese hamster ovary; HEK, human embryonic kidney; [³H](+)-PHNO, [³H](+)-trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-propyl-4H-naphtho[1,2-b]-1,4-oxazine.

Disclosure

Neither honoraria nor payments were made for authorship. All authors are or were employees of Gedeon Richter Plc. Mr. Béla Kiss, Dr. István Laszlovszky and Dr. Katalin Sághy are inventors of cariprazine and received a personal fee for it. Dr. István Gyertyán is an inventor of cariprazine and is entitled to receive a personal fee for it. All authors report nonfinancial support from Prescott Medical Communication Group for editorial assistance during preparation of the manuscript. The authors report no further conflicts of interest in this work.