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

Abstract

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.

Enhanced efficacy of AZD3759 and radiation on brain metastasis from EGFR mutant non‐small cell lung cancer

“…The activity of AZD3759 in brain was evaluated by detecting the extent and duration of pEGFR reduction relative to the free concentration of AZD3759 in brain …”

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

“…A series of modeling studies was undertaken to predict active doses of osimertinib in humans by incorporating human PK data into a previously developed PK-pharmacodynamic (PKPD) PC9 subcutaneous xenograft efficacy model that linked phosphorylated EGFR (pEGFR) inhibition to reductions in tumor volume (34). The studies also accounted for reduced free concentrations in the brain due to higher levels of binding than observed in plasma.…”

Development and validation of a UPLC–MS/MS method for quantification of osimertinib (AZD9291) and its metabolite AZ5104 in human plasma

“…Although several simultaneous pharmacokinetic studies of osimertinib, AZ5104 and AZ7750 were reported in papers, as well as the quantification methods for simultaneous determination of osimertinib and its active metabolites (Brown et al, ; Planchard et al, ; Yates et al, ; Zhao et al, ), details of these assays were, other than the use of protein precipitation, electrospray ionization and a labeled compound as internal standard (IS), never reported. Recently, a method reported by Vishwanathan et al () showed that the accuracy ranged from 93.5 to 123.7%, which was not suitable for PK studies.…”