Table 2.
Summary of SPI-1865 PK/PD studies in wild-type and transgenic mouse and wild-type rat
| Species and dosing regime | Dose (mg/kg) | Tissue | Plasma exposure (μM) | Brain exposure (μM) | %Aβ38 lowering | %Aβ40 lowering | %Aβ42 lowering | Collection time (hrs) |
|---|---|---|---|---|---|---|---|---|
| Wild-type rat single dose | 10 | Brain | 3.3 ± 0.1 | 2.8 ± 0.3 | 26 ± 5 | 1 ± 5 | 21 ± 6* | 24 |
| 30 | Brain | 8.5 ± 0.3 | 11 ± 1 | 36 ± 3* | 14 ± 4 | 37 ± 5* | 24 | |
| 100 | Brain | 14 ± 1 | 33 ± 2 | 47 ± 5* | 22 ± 5* | 50 ± 5* | 24 | |
| Wild-type rat multiple doses | 10 | Brain | 8.0 ± 0.4 | 4.4 ± 0.2 | 27 ± 3* | 1 ± 2 | 24 ± 2* | 24 |
| 30 | Brain | 13 ± 1 | 16 ± 1 | 49 ± 2* | 8 ± 3 | 44 ± 2* | 24 | |
| 60 | Brain | 19 ± 1 | 45 ± 4 | 61 ± 2* | 26 ± 2* | 66 ± 1* | 24 | |
| Tg2576 mouse multiple doses | 10 | Brain | 1.1 ± 0.2 | 0.5 ± 0.1 | -16 ± 12 | -14 ± 11 | -9 ± 10 | 24 |
| 30 | Brain | 2.5 ± 0.1 | 1.3 ± 0.1 | 6 ± 9 | 6 ± 9 | 7 ± 9 | 24 | |
| 60 | Brain | 5.4 ± 0.5 | 3.9 ± 0.4 | 14 ± 10 | 2 ± 10 | 19 ± 8 | 24 | |
| 90 | Brain | 6.4 ± 0.5 | 6.9 ± 0.6 | 27 ± 8 | 8 ± 9 | 30 ± 6 | 24 | |
| 10 | Plasma | 1.1 ± 0.2 | 0.5 ± 0.1 | 25 ± 5 | 6 ± 7 | 25 ± 5* | 24 | |
| 30 | Plasma | 2.5 ± 0.1 | 1.3 ± 0.1 | 26 ± 5 | 17 ± 5 | 58 ± 3* | 24 | |
| 60 | Plasma | 5.4 ± 0.5 | 3.9 ± 0.4 | 50 ± 5* | 15 ± 7 | 71 ± 2* | 24 | |
| 90 | Plasma | 6.4 ± 0.5 | 6.9 ± 0.6 | 46 ± 6* | 9 ± 6 | 76 ± 2* | 24 | |
| 10 | CSF | 1.1 ± 0.2 | 0.5 ± 0.1 | -2 ± 9 | -3 ± 9 | 1 ± 11 | 24 | |
| 30 | CSF | 2.5 ± 0.1 | 1.3 ± 0.1 | 4 ± 10 | 0 ± 11 | 6 ± 11 | 24 | |
| 60 | CSF | 5.4 ± 0.5 | 3.9 ± 0.4 | 5 ± 9 | -7 ± 12 | 22 ± 15 | 24 | |
| 90 | CSF | 6.4 ± 0.5 | 6.9 ± 0.6 | 9 ± 11 | 10 ± 13 | 33 ± 14 | 24 | |
| Wild-type mouse multiple twice-daily doses | 15 | Brain | 3.4 ± 0.2 | 3.6 ± 0.1 | 13 ± 4 | 3 ± 2 | 22 ± 4* | 6 |
| 30 | Brain | 4.4 ± 0.3 | 8.7 ± 1.0 | 30 ± 3* | 11 ± 2* | 39 ± 3* | 6 | |
| 50 | Brain | 7.6 ± 0.3 | 22 ± 1 | 28 ± 2* | 9 ± 2 | 47 ± 2* | 6 |
The pharmacokinetic and pharmacodynamic properties of SPI-1865 were assessed in mouse and rat model systems. *Statistically significant lowering of the indicated β-amyloid (Aβ) species compared to vehicle-treated animals (P < 0.01). CSF, cerebrospinal fluid. Values are given as the mean ± standard error of the mean.