Table 3. Pharmacokinetics, in Vitro ADMEa Properties, and in Vivo Efficacy of 2q.
| IV dose (1 mg/kg) |
PO dose (3 mg/kg) |
||||||
|---|---|---|---|---|---|---|---|
| species | AUC0-inf (ng*h/mL) | CL (mL/min/kg) | Vdss (mL/kg) | t1/2 (h) | AUC0-inf (ng*h/mL) | Cmax (ng/mL) | F (%) |
| rat | 703 | 24.0 | 995 | 0.85 | 1038 | 618 | 49 |
| dog | 1500 | 6.7 | 279 | 0.52 | 359 | 1110 | 19 |
| species | microsomes predicted CLb (mL/min/kg) | hepatocytes predicted CLc (mL/min/kg) | protein binding (%) | CYP450d IC50 (μM) | PAMPA permeability × 10−6 cm/s |
|---|---|---|---|---|---|
| mouse | 5.8 | 14 | 81.8 | na | 49 |
| rat | 5.3 | 16 | 78.0 | na | |
| dog | 3.8 | 12 | 68.8 | na | |
| human | <0.7 | <0.6 | 88.8 | all > 10 |
| in vivo efficacy model | ED50 (mg/kg/day) | ED90 (mg/kg/day) | ED99 (mg/kg/day) |
|---|---|---|---|
| P. berghei ANKA | 13 | 28 | 62 |
| P. falciparum 3D70087/N9 | 13 | 27 | 60 |
a
Assay conditions reported in ref (10).
b
Using well-stirred model with correction for microsomal and protein binding.
c
Using well-stirred model with correction for protein binding.
d
CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP2D6 were evaluated.