Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic-Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104

Mol Cancer Ther. 2016 Oct;15(10):2378-2387. doi: 10.1158/1535-7163.MCT-16-0142. Epub 2016 Jul 20.


Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378-87. ©2016 AACR.

MeSH terms

  • Acrylamides
  • Algorithms
  • Aniline Compounds
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Line, Tumor
  • Disease Models, Animal
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • Humans
  • Mice
  • Models, Biological
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Xenograft Model Antitumor Assays


  • Acrylamides
  • Aniline Compounds
  • Antineoplastic Agents
  • Piperazines
  • Protein Kinase Inhibitors
  • osimertinib
  • ErbB Receptors