Фармакодинамика антипсихотика SB-773812

The aim of this study was to assess human striatal dopamine receptor 2 (D2) and cortical 5-hydroxytryptamine receptor 2A (5-HT2A) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics–receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.
Methods: D2 and 5-HT2A occupancy were measured over time (both at the time of maximum [Tmax; 6 6 2 h] and at the time of minimum [Ttrough; 24 6 4 h] plasma concentration after dosing) by means of 123I-iodobenzamide and 123I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (123I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers—D2 occupancy measured at 48 (n 5 9) and 56 mg (n 5 9) and 5-HT2A occupancy at 56 mg (n 5 9); study B consisted of D2 and 5-HT2A occupancy measured in 12 stabilizedschizophrenia patients on stable doses (16–18 d of 56 mg/d) after washout of previous medication; and study C included D2 occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n 5 10) on stable doses (18–21 d) of SB-773812 (100 mg/d; n 5 7) or risperidone (6 mg/d; n 5 3).
Results: Study A showed less than 30% D2 occupancy at Tmax, maintained at Ttrough. 5-HT2A occupancy was 74%–97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D2 occupancy. 5-HT2A occupancy ranged from 91% to 100%. In study C, SB-773812–induced D2 occupancy was 60.3% 6 13.3% at Tmax and 55.1% 6 4.9% at Ttrough. The pharmacokinetics–receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC50) of 92.7 6 13.5 ng/mL for D2 and 2.11 6 0.50 ng/mL for 5-HT2A.
Conclusion: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D2 occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics–receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.

 Contribution of SPECT Measurements of D2 and 5-HT2A Occupancy to the Clinical Development of the Antipsychotic SB-773812