Journal Article

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

Huang, Xiangning, Tomkinson, Helen, Vishwanathan, Karthick, Rukazenkov, Yuri, Lin, Yu‐Wei, Johnson, Martin, Sunnaker, Mikael, Schmidt, Henning, Van Maanen, Eline

2025

Overview

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. Osimertinib has proven efficacy in EGFR mutation‐positive NSCLC; a popPK model was previously developed using data from 2nd‐/later‐line settings. We updated this model with additional data, confirming that a fixed 80 mg once‐daily dose is optimal for osimertinib across all lines of treatment.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acrylamides - administration & dosage / Acrylamides - pharmacokinetics / Adult / Aged / Aged, 80 and over / Aniline Compounds - administration & dosage / Aniline Compounds - pharmacokinetics / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacokinetics / Approximation / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - metabolism / covariates / Epidermal growth factor / ErbB Receptors - antagonists & inhibitors / Female / Humans / Indoles / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - metabolism / Male / Metabolites / Metastasis / Middle Aged / modeling / Models, Biological / Monte Carlo Method / Mutation / Original / osimertinib / Parameter estimation / Patients / Pharmacokinetics / population pharmacokinetics / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - pharmacokinetics / Pyrimidines / race / simulation