Bridging the Gap between Preclinical and Clinical Studies Using Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling: An Analysis of GDC-0973, a MEK Inhibitor

Purpose: GDC-0973 is a potent and selective MEK inhibitor. Pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics (PD) and anti-tumor efficacy in order to establish pharmacokinetic endpoints and predict active doses in the clinic. Experimental Design: A PK-PD model was used to characterize GDC-0973 tumor disposition and in vivo potency in WM-266-4 xenograft mice. Simulations were performed using the PK-PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and anti-tumor efficacy was characterized in A375 melanoma xenograft mice, and a population based integrated PK-PD-efficacy model was used to relate tumor PD (%pERK decrease) to anti-tumor activity. Results: GDC-0973 showed a sustained tumor PD response due to longer residence in tumor than plasma. Following single doses of GDC-0973, estimated in vivo IC50 of %pERK decrease based on tumor concentrations in xenograft mice was 0.78 (WM-266-4) and 0.52 μM (A375). Following multiple doses of GDC-0973, the estimated in vivo IC50 in WM-266-4 increased (3.89 μM). Human simulations predicted a minimum target plasma concentration of 83 nM and an active dose range of 28-112 mg. The steep relationship between tumor PD (%pERK decrease) and anti-tumor efficacy suggests a pathway modulation threshold beyond which anti-tumor efficacy switches on. Conclusions: Clinical observations of %pERK decrease and anti-tumor activity were consistent with model predictions. This manuscript illustrates how PK-PD modeling can improve the translation of preclinical data to man by providing a means to integrate preclinical and early