TABLE 3

Comparison of pharmacokinetic parameters of dabrafenib in FVB wild-type and Mdr1a/b−/−Bcrp1−/− mice after an i.v. dose of 2.5 mg/kg

Wild TypeMdr1a/b−/−Bcrp1−/− Mice
PlasmaBrainPlasmaBrain
Terminal rate constant (min−1)0.030.0360.0240.026
Half-life (min)23.719.128.326.6
Clearance (ml/min/kg)24.228.4
Volume of distribution (l/kg)0.831.2
AUC0 → t last (µg · min /ml)a120.9 ± 15.82.8 ± 0.4101.4 ± 8.742.1 ± 3.4b
Kp0.0230.42
Kp ratioc18.3

  • AUC, area under the concentration-time curve; FVB, Friend leukemia virus strain B; Kp, AUCbrain/AUCplasma.

  • ↵a Area under the curve from time zero to 2 hours postdose.

  • ↵b P < 0.05 compared with wild-type AUCbrain.

  • ↵c Kp ratio = (Kp in Mdr1a/b−/−Bcrp1−/− mice) / (Kp in wild-type mice).