Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor

Clin Cancer Res. 2012 Jun 1;18(11):3090-9. doi: 10.1158/1078-0432.CCR-12-0445. Epub 2012 Apr 10.

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 IC(50) 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 IC(50) 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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology*
  • Cell Line, Tumor
  • Humans
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / pharmacokinetics
  • Mitogen-Activated Protein Kinase Kinases / pharmacology
  • Models, Biological
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Azetidines
  • Piperidines
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase Kinases
  • cobimetinib