P.3.c.053 Dopamine D2/D3 receptor occupancy of RGH-188, a D3/D2 antagonist/partial agonist antipsychotic, in healthy volunteers

Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

“…5-HT1A receptor occupancy was considerably lower compared with D2/D3 occupancy at the same doses [9]. 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].…”

“…The pharmacodynamic profile of cariprazine was further characterized using positron emission tomography (PET) in monkeys [9], human volunteers [39], and persons with schizophrenia [40,41]. In monkey brains, cariprazine occupied D2 and D3 receptors in a dose-dependent and saturable manner [9].…”

Cariprazine, a new, orally active dopamine D2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

“…Studies in rodents reveal that chronic administration of cariprazine, like haloperidol and other antipsychotics, both typical and atypical, inhibits the spontaneous activity of dopaminergic neurons in the ventral tegmental area in a dose-dependent manner [36]. However, cariprazine differs from haloperidol in failing to decrease the number of spontaneously active neurons in the substantia nigra pars compacta, a property shared with some other atypical antipsychotics such as clozapine.…”

“…Following the nonhuman primate PET studies, striatal D 2/3 receptor occupancy by cariprazine was determined with [ 11 C] raclopride in healthy volunteers [35,36]. Single oral doses of 0.5 mg cariprazine occupied up to 12% of striatal D 2/3 receptors, whereas striatal D 2/3 occupancy after multiple dosing 0.5 mg cariprazine for the first 2 days and 1.0 mg for the subsequent 12 days ranged between 63 and 79%, that is, the range of occupancies reported for typical antipsychotic drugs.…”

Cariprazine for the Treatment of Bipolar Disorder

“…This profile is similar to aripiprazole, except that the affinity for D3 is greater than for D2, and is so high that extremely small doses are sufficient to get maximal D3 occupancy (Kiss et al., ). Doses of 1 mg daily are sufficient to achieve the therapeutic level of over 65% receptor occupancy (Laszlovsky et al., ). Doses of 1.5 mg daily achieve 69–75% receptor occupancy in subjects with schizophrenia (Potkin et al., ).…”