A population pharmacokinetic (PK) model for erlotinib (E), a small molecule inhibitor of the epidermal growth factor receptor (EGFR)

Abstract

2032 Background: E as a single agent produced a survival benefit in patients with advanced NSCLC after failure of at least one prior chemotherapy regimen. The objective of this analysis was to: 1) describe the PK of E and its active metabolite (OSI-420) using a population approach and 2) identify covariates that impact E PK. Methods: A population PK model was developed using 2670 E concentrations from 708 patients enrolled in 4 Phase II single-agent trials and 2 Phase III trials in combination with chemotherapy. A subsequent analysis was performed using 2576 concentrations in 591 patients from 4 phase II single agent study plus a single-agent Phase III NSCLC trial once its data became available. Results: A one-compartment model described the concentration data well. The covariate effects were similar between the two analyses, where total bilirubin, α-1-glycoprotein, and smoking status were the most important factors affecting clearance (CL/F). The overall contribution of these covariates was modest and may not be clinically relevant considering the large inter-patient variability observed for CL/F (∼50%). Other factors such as chemotherapy, sex, alkaline phosphatase, albumin, and creatinine clearance were also statistically significant effects (p < 0.005), but their overall influence on E PK was small and their estimated coefficient of variation (CV) was large. From single-agent data, the CL/F and volume of distribution (Vc/F) for a typical patient were 3.95 L/hr and 233 L, respectively. Based on the individual PK parameters from 591 patients, the predicted means (± SD) for the steady-state AUCSS, and Cmin,SS were 41.3 ± 22.0 μg/mL · hr, and 1240 ± 826 ng/mL, respectively. Median t1/2 was 36.2 hours in these patients. Conclusions: The long half-life and the modest effects of covariates on CL/F of erlotinib support the current recommended dosing regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche, Genentech, OSI Hoffmann-La Roche, Genentech, OSI