TABLE 3

Terminal plasma concentrations and target coverage multiples over the mNaV1.7 IC50 (Cu/mPX IC50) for AMG8379 and AMG8380 from behavioral experiments

Values in bold indicate target coverage multiples that significantly affected behavioral endpoints. Values are expressed as the mean ± SEM.

ExperimentCompoundDose (mg/kg)Plasma (μM)Plasma Cu (μM)Cu/mPX IC50
Open-field activity (Fig. 8)AMG83791013.7 ± 0.7660.024 ± 0.0011.7 ± 0.09
AMG83793047.1 ± 2.450.081 ± 0.0045.84 ± 0.305
AMG8379100189.4 ± 13.30.326 ± 0.02323.5 ± 1.65
Histamine (Fig. 9A)AMG83791010.6 ± 1.140.018 ± 0.0021.32 ± 0.141
AMG83793042.7 ± 8.260.073 ± 0.0145.3 ± 1.03
AMG8379100174.1 ± 7.980.3 ± 0.01421.6 ± 0.99
Histamine (Fig. 9B)AMG8380105.31 ± 0.8480.073 ± 0.0120.18 ± 0.030
AMG83803033.8 ± 4.960.466 ± 0.0681.20 ± 0.177
AMG8380100123.2 ± 7.921.70 ± 0.1094.39 ± 0.283
AMG8379100120.7 ± 4.290.207 ± 0.00714.9 ± 0.527
UVB (Fig. 10A)AMG83791025.1 ± 5.840.043 ± 0.0103.11 ± 0.723
AMG83793088.6 ± 8.670.153 ± 0.01510.9 ± 1.08
AMG8379100186.0 ± 16.10.321 ± 0.02823.1 ± 1.98
AMG8380100190.8 ± 19.62.63 ± 0.2716.80 ± 0.699
Capsaicin (Fig. 10B)AMG83793055.7 ± 2.730.096 ± 0.0056.90 ± 0.339
AMG8379100171.1 ± 16.20.295 ± 0.02821.2 ± 2.01
  • Cu, free drug concentration; histamine, histamine-induced scratch; UVB, UVB-induced thermal hyperalgesia; capsaicin, capsaicin-induced licking. AMG8379: fu = 0.245%; mNaV1.7 IC50 (PatchXpress) = 0.0186 μM. AMG8380: fu = 1.38%; mNaV1.7 IC50 (PatchXpress) = 0.387μM.