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

Abstract

Abstract Purpose: GDC-0973 is a potent and selective mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibitor. Pharmacokinetic–pharmacodynamic (PK–PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics and antitumor efficacy 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 conducted using the PK–PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and antitumor efficacy were characterized in A375 melanoma xenograft mice, and a population-based integrated PK–PD-efficacy model was used to relate tumor pharmacodynamics (%pERK decrease) to antitumor activity. Results: GDC-0973 showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma. Following single doses of GDC-0973, estimated in vivo IC50 values of %pERK decrease based on tumor concentrations in xenograft mice were 0.78 (WM-266-4) and 0.52 μmol/L (A375). Following multiple doses of GDC-0973, the estimated in vivo IC50 value in WM-266-4 increased (3.89 μmol/L). Human simulations predicted a minimum target plasma concentration of 83 nmol/L and an active dose range of 28 to 112 mg. The steep relationship between tumor pharmacodynamics (%pERK decrease) and antitumor efficacy suggests a pathway modulation threshold beyond which antitumor efficacy switches on. Conclusions: Clinical observations of %pERK decrease and antitumor activity were consistent with model predictions. This article illustrates how PK–PD modeling can improve the translation of preclinical data to humans by providing a means to integrate preclinical and early clinical data. Clin Cancer Res; 18(11); 3090–9. ©2012 AACR.