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Table 2 Summary of SPI-1865 PK/PD studies in wild-type and transgenic mouse and wild-type rat

From: Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models

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
  1. 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.