FIGURE 1.

Final population PK model for regorafenib, M‐2 and M‐5, incorporating enterohepatic circulation. Volume and flow parameters are relative, and apparent clearances and volume of distribution are shown. Gallbladder emptying for parent regorafenib is described by the following equations (this also occurs in the model for M‐2 and M‐5, but these similar equations are not presented here):

Not during meal:

dA₃/dt = k _a A₂ – k _CG A₃ – (CL_P/VC_P) A₃ – (Q_P/VC_P) A₃ + (Q_P/VP_P) A₅

dA₄/dt = k _CG A₃

During meal:

dA₃/dt = k _a A₂ – k _CG A₃ – (CL_P/VC_P) A₃ – (Q_P/VC_P) A₃ + (Q_P/VP_P) A₅ + A₄ k _GE

dA₄/dt = k _CG A₃ – A₄ k _GE

A3, parent amount in central compartment; A4, parent amount in gallbladder compartment; A5, parent amount in peripheral compartment; CG, central compartment to gallbladder; CL_P/CL_M‐2/CL_M‐5, apparent parent/M‐2/M‐5 clearance; FRM2/5, fraction of formation of metabolite M‐2/M‐5; F1, oral bioavailability; GE, gallbladder emptying; k, rate constant; k _a, absorption rate constant; PK, pharmacokinetic; Q, intercompartmental clearance; Trans, transit compartment; VC, central compartment volume; VP, peripheral compartment volume