Development of a Population-based Pharmacokinetic-pharmacodynamic Model to Simulate Treatment Efficacy in Metastatic non-small-cell Lung Cancer Patients on Erlotinib

Erlotinib improves progression-free survival (PFS) in metastatic non-small-cell lung cancer (mNSCLC) patients, but cause toxicities leading to dose reductions. The survival impact of dose reductions is unknown. We constructed a population-based pharmacokinetic-pharmacodynamic (PK-PD) erlotinib model predicting PFS of mNSCLC patients, consisting of an erlotinib population PK component, a PD component describing the concentration-kill-constant relationship, and a tumour growth component tracking tumour size over time. This model was fit against clinical trial data to simulate population-based PFS estimates in mNSCLC patients and externally validated using other trial data. The model simulated population-based PFS estimates of placebo and erlotinib arms with 0.74-9.14% and 0.26-19.83% error, respectively. The model was externally validated with population-based PFS estimate errors of 11.3% and 16.7% in epidermal growth factor receptor (EGFR)-mutant and EGFR-wild-type mNSCLC, respectively. It predicted significant PFS decreases with dose reductions. This is the first population-based PK-PD erlotinib model that predicts PFS in mNSCLC patients.M.Sc.2016-12-21 00:00:0