Population Pharmacokinetics of Osimertinib in Patients With Non-Small Cell Lung Cancer.

Population pharmacokinetics (popPK) modeling for osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing mutations and EGFR T790M, was previously reported utilizing AURA and AURA2 data (advanced non-small cell lung cancer [NSCLC]). We report updated popPK modeling incorporating AURA3 and FLAURA data (advanced NSCLC); model validation used ADAURA data (resected stage IB-IIIA NSCLC). Updated popPK analyses were based on patients from AURA (n = 599), AURA2 (n = 210), AURA3 (n = 277), and FLAURA (n = 278) using a linear one-compartmental disposition model for osimertinib and its metabolite, AZ5104, with first-order oral absorption. A full covariate model, using Monte Carlo simulations, was developed to assess the effects of covariates on osimertinib and AZ5104 clearance. External validation was conducted using ADAURA study data (n = 325). In the final popPK model, the apparent clearance and volume of distribution of osimertinib (14.3 L/h; 918 L) and AZ5104 (31.3 L/h; 143 L) were comparable to previous analyses. Albumin levels and body weight influenced osimertinib PK, but the effects were not considered clinically meaningful; other covariates had no impact on PK. Goodness-of-fit plots indicated that the model adequately described all data. Visual predictive checks showed that the final model validated osimertinib steady-state PK for adjuvant treatment. PopPK modeling indicated that osimertinib dose adjustment is not required for patients' age, sex, body weight, race, smoking status, or line of therapy, confirming that a fixed 80 mg once-daily dose is optimal for osimertinib.