Table 3. Occupancy model estimates.
| Constraint | Method | Regions | Cort EC50 | STR EC50 | Cort OCCMAX (%) | STR OCCMAX (%) | AICC | 10 mg occ. in humans (%) |
|---|---|---|---|---|---|---|---|---|
| No constraint | 2TC | Both | DNC | 214.0 | DNC | 53.83 | a32.16 | 0.13 |
| Global EC50 | 2TC | Both | 259.6 | 259.6 | 18.3 | 63.9 | 62.98 | 0.13 |
| No constraint | SRTM | Both | 160.9 | 154.1 | 27.37 | 54.09 | 52.14 | 0.18 |
| Global EC50 | SRTM | Both | 154.7 | 154.7 | 26.9 | 54.18 | 47.43 | 0.18 |
| Str 100% | 2TC | STR | 530.2 | 100 | 30.18 | 0.10 | ||
| Str 100% | SRTM | STR | 464.7 | 100 | 25.02 | 0.11 | ||
| Ratio constraint | 2TC | Both | 546.5 | 31 | 100 | 56.64 | 0.10 | |
| Ratio constraint | SRTM | Both | 471.1 | 51 | 100 | 44.00 | 0.11 |
AICC, Akaike information criterion; Cort, cortex; DNC, did not converge; SRTM, simplified reference tissue method; STR, striatum; 2TC, two-tissue compartment.
All concentrations are in ng/mL.
AICC for the 2TC unconstrained model is for the striatum only owing to the nonconvergence in the cortex; i.e., it is directly comparable only with the 2TC striatum fit with OCCMAX=100% constraint. AICC is displayed in ‘less is better' form, and direct comparisons are only valid for models using the same data. Human occupancy estimates (column 9) represent the estimated fraction of all D1 receptors bound by DAR-0100A after a 10 mg infusion. These were derived by application of equation (4), using the observed arterial plasma concentration measured in n=2 human subjects who received 10 mg infusions of DAR-0100A, the EC50 and maximal occupancy estimates in the striatum (columns 5 and 7) and the ratio of plasma free fraction of DAR-0100A in humans to that in baboons (3/8).