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To evaluate the striatal D3/D2 receptor occupancy of cariprazine (RGH-188) in healthy volunteers and schizophrenic patients, and assess the correlation between cariprazine plasma concentration and receptor occupancy.
Single- (0.5 mg) or multiple-dose (1 mg/day, 14 days) cariprazine was administered to healthy adult males (N=5) in an open-label positron emission tomography (PET) study. In a separate open-label PET study, multiple-dose cariprazine (0.5-3.0 mg/day, 14 days) was administered to adult male schizophrenic patients (N=8). Healthy volunteers had 1 predose and 1 postdose raclopride PET scan; schizophrenic patients had 1 predose and up to 3 postdose fallypride scans. Cariprazine plasma concentrations were determined by LC-MS/MS.
In healthy volunteers, single-dose cariprazine 0.5 mg resulted in low plasma concentration (0.1 ng/ml) and was associated with 12% maximum D3/D2 receptor occupancy; cariprazine 1 mg/day for 14 days resulted in cariprazine plasma concentrations of 2.3-3.4 ng/ml and >70% D3/D2 receptor occupancy. In schizophrenic patients, cariprazine 1.5 mg/day for 14 days resulted in cariprazine plasma concentrations of 2.5-3.4 ng/ml and >70% receptor occupancy; cariprazine 3.0 mg/day resulted in ≥90% occupancy. Predicted Emax values in schizophrenic patients approached 100% D3/D2 occupancy for dorsal and ventral striatum.
D3/D2 receptor occupancy in dorsal and ventral striatum was similar for cariprazine 1.0 mg/day in healthy volunteers and cariprazine 1.5 mg/day in schizophrenic patients. In both, higher receptor occupancy was associated with higher cariprazine plasma concentration. Cariprazine at 1.5 to 3.0 mg/day showed D3/D2 receptor occupancy within the predicted effective antipsychotic range.
RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.
RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.
RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.
In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.
After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.
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