TABLE 1

PK parameters of cobimetinib observed in FVB (WT; n = 6), CYP3a KO (n = 3) and CYP3A4 transgenic mice (n = 3) after i.v. (1 mg/kg) and oral (5 mg/kg) administration of cobimetinib

Mouse Type/PK Parameter	FVB	Cyp3a^−/−	Cyp3a^−/−Tg-3A4_Hep	Cyp3a^−/−Tg-3A4_Int	Cyp3a^−/−Tg-3A4_Hep/Int
i.v.
CL (ml/min/kg)	28.2 ± 4.4	20.8 ± 2.6	30.7 ± 4.6	25.9 ± 1.1	34.8 ± 12.5
V_ss (l/kg)	15.3 ± 3.5	10.4 ± 0.9	12.2 ± 1.7	16.0 ± 1.0	13.8 ± 7.6
t_1/2 (hour)	7.52 ± 3.02	6.14 ± 1.38	4.96 ± 0.37	7.94 ± 0.67	5.09 ± 1.93
E	0.313 ± 0.048	0.231 ± 0.029	0.341 ± 0.051	0.288 ± 0.012	0.386 ± 0.138
F_h	0.687 ± 0.048	0.769 ± 0.029	0.659 ± 0.051	0.712 ± 0.012	0.614 ± 0.138
Oral
AUC (μM.h)	1.38 ± 0.25	6.42 ± 1.07^{^a}	3.39 ± 1.43^{^b}	1.04 ± 0.11^{^c}	0.701 ± 0.087^{^c}
C_max (μM)	0.175 ± 0.041	0.479 ± 0.077	0.372 ± 0.148	0.080 ± 0.011	0.107 ± 0.011
F (%)	29	84	65	17	14

↵^a P < 0.05 compared with FVB.
↵^b P < 0.05 compared with Cyp3a KO.
↵^c P < 0.05 compared with Cyp3a KO and Cyp3a^−/−Tg-3A4_Hep.