Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation

Clin Cancer Res. 2011 Jul 15;17(14):4682-92. doi: 10.1158/1078-0432.CCR-11-0975. Epub 2011 May 24.

Abstract

Purpose: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic-pharmacodynamic (PK/PD) relationship of vismodegib in both model systems to guide optimal dose and schedule for vismodegib in the clinic.

Experimental design: Preclinical efficacy and PK/PD studies were carried out with vismodegib in a Ptch(+/-) allograft model of medulloblastoma exhibiting mutational activation of the Hh pathway and patient-derived colorectal cancer (CRC) xenograft models exhibiting ligand-dependent pathway activation. Inhibition of the hedgehog pathway was related to vismodegib levels in plasma and to antitumor efficacy using an integrated population-based PK/PD model.

Results: Oral dosing of vismodegib caused tumor regressions in the Ptch(+/-) allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC(50) in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of vismodegib is associated with >80% repression of the Hh pathway.

Conclusions: These results suggest that even small reductions in vismodegib exposure can lead to large changes in antitumor activity and will help guide proper dose selection for vismodegib in the clinic.

MeSH terms

  • Anilides / administration & dosage
  • Anilides / pharmacokinetics*
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Ligands
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism
  • Mice
  • Mice, Nude
  • Models, Biological
  • Mutation
  • Pyridines / administration & dosage
  • Pyridines / pharmacokinetics*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • Zinc Finger Protein GLI1

Substances

  • Anilides
  • Antineoplastic Agents
  • GLI1 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • Ligands
  • Pyridines
  • Transcription Factors
  • Zinc Finger Protein GLI1