TABLE 2

Effect of inhibitors (itraconazole) and inducers (rifampin) of CYP3A on the PK and exposure (mean ± S.D.; n = 3–6/group) of cobimetinb in Cyp3a−/−Tg-3A4Hep/Int and PXR-CAR-CYP3A4/3A7 mice

Cyp3a−/−Tg-3A4Hep/Int (Itraconazole Study)PXR-CAR-CYP3A4/3A7 (Rifampin Study)
No TreatmentIntraconzoleVehicleRifampin
Cobimetinib (oral)
 AUC(0-tlast) (μM.h)0.701 ± 0.0875.86 ± 0.21*3.95 ± 0.580.854 ± 0.278*
 Cmax (μM)0.107 ± 0.0110.333 ± 0.010*0.369 ± 0.0850.142 ± 0.058*
Cobimetinib (i.v.)
 AUC(0-inf) (μM.h)1.01 ± 0.463.73 ± 0.93*
 CL (ml/min/kg)34.8 ± 12.58.71 ± 2.01*
 T1/2 (hour)5.09 ± 1.9322.5 ± 6.6*
  • * P < 0.05 compared with corresponding control animals.