Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human

Xenobiotica. 2011 Dec;41(12):1088-99. doi: 10.3109/00498254.2011.603386. Epub 2011 Aug 13.


The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation is associated with the development of many cancers. GDC-0941, a potent and selective inhibitor of PI3K, was characterised preclinically in in vitro and in vivo studies. Plasma protein binding was extensive, with free fraction less than 7%, and blood-to-plasma ratio ranged from 0.6 to 1.2 among the species tested. GDC-0941 human hepatic clearance was predicted to be moderate by liver microsomal incubations. GDC-0941 had high permeability in Madin-Darby canine kidney cells. The clearance of GDC-0941 was high in mouse (63.7 mL/min/kg), rat (49.3 mL/min/kg) and cynomolgus monkey (58.6 mL/min/kg), and moderate in dog (11.9 mL/min/kg). The volume of distribution ranged from 2.52 L/kg in rat to 2.94 L/kg in monkey. Oral bioavailability ranged from 18.6% in monkey to 77.9% in mouse. Predicted human clearance and volume of distribution using allometry were 6 mL/min/kg and 2.9 L/kg, respectively. The human efficacious doses were predicted based on results from preclinical pharmacokinetic studies and xenograft models. GDC-0941 preclinical characterisation and predictions of its properties in human supported its progression towards clinical development. GDC-0941 is currently in phase II clinical trials.

MeSH terms

  • Administration, Oral
  • Animals
  • Area Under Curve
  • Autoradiography
  • Carbon Radioisotopes
  • Cell Line
  • Cell Membrane Permeability
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / blood
  • Indazoles / chemistry
  • Indazoles / pharmacokinetics*
  • Male
  • Microsomes, Liver / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Species Specificity
  • Sulfonamides / administration & dosage
  • Sulfonamides / blood
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics*
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
  • Carbon Radioisotopes
  • Indazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Phosphatidylinositol 3-Kinase