Cariprazine: A new antipsychotic waiting approval:Expert Opin Drug Meta Toxi. 2013. Feb


Cariprazine is a new second-generation antipsychotic in late stage of clinical development.Application for approval ( acute indications of schizophrenia and bipolar mania/mixed episodes)  is waiting FDA decision. As of Nov 2012, the clinical trials website shows 18 separate records of ongoing trials. ( ).

Cariprazine is a dopamine D3 preferring D3/D2 receptor partial agonist.It  is an antagonist in systems with normal dopaminergic activity, but is a partial agonist when dopaminergic tone is reduced . When  compared with aripiprazole, it has  similar D2 and higher D3 antagonist-partial agonist affinity and a 3– to 10-fold greater D3 vs. D2 selectivity was observed for cariprazine .

Receptor occupancy in striatal regions reaches 90% or more at 3mg dose for 14 days.After single dose administration, Cmax for cariprazine was 3 – 4 h under fasting conditions. The mean half-life for cariprazine was 2 – 5 days over a dose range of 1.5 – 12.5 mg. Steady- state plasma concentrations of cariprazine were reached within 1 week.Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. Metabolite,didesmethyl- cariprazine has a longer elimination half-life.

Clinical trials:

Results of four Phase II or III 6-week randomized controlled trials in acute schizophrenia are available, in which three studies are positive for cariprazine at all doses tested.   The first reported Phase II trial had 389 adults with an acute exacerbation of schizophrenia who were randomized to receive up to 6 weeks of double-blinded cariprazine low dose (1.5 – 4.5 mg/d), cariprazine high dose (6 – 12 mg/d), or placebo  .The change from baseline to Week 6 in PANSS total score was -9.7, -14.5, and -12.6 for the placebo, cariprazine low-dose, and high-dose groups, respectively  (Litman 2008).Another  Phase II trial with 732 adults with acute schizophrenia were randomized to 6 weeks of double-blind treatment with fixed doses of cariprazine 1.5 mg, 3.0 mg, or 4.5 mg/d , risperidone 4.0 mg/d , or placebo.Improvement in PANSS total score at Week 6 was greater for cariprazine 1.5, 3.0, and 4.5 mg/d vs. placebo .No clinically relevant changes were noted for cariprazine on metabolic variables, prolactin levels, or the ECG QT interval (Bose  2010).

Would targeting D3 be of benefit? :  This remains unknown.The D3 receptor is an autoreceptor that controls the phasic, but not tonic, activity of dopamine neurons and mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade. Dopamine D3 preferring agents may exert pro-cognitive effects.

Better than aripiprazole?   We will have to wait to know this. 

Other benefits: The metabolite,didesmethyl-cariprazine has  terminal half-life of 2 – 3 weeks  and this may allow for the development of a once-weekly oral formulation.

Caution: Caution should be exercised when interpreting the clinical trial results as presented in posters and press releases as they may represent preliminary results and may differ from what is eventually published in a peer-reviewed study report. The clinical data available is incomplete as well.

Summary of the article:

Cariprazine : chemistrypharmacodynamicspharmacokinetics, and metabolismclinical efficacysafety, and tolerability.

Citrome L.Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206.

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