Johnson Martin, Lin Yu-Wei, Schmidt Henning, Sunnaker Mikael, Van Maanen Eline, Huang Xiangning, Rukazenkov Yuri, Tomkinson Helen, Vishwanathan Karthick
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Science, R&D, AstraZeneca, Cambridge, UK.
Certara, Radnor, Pennsylvania, USA.
Pharmacol Res Perspect. 2025 Jun;13(3):e70098. doi: 10.1002/prp2.70098.
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.
奥希替尼是一种第三代不可逆口服表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），可有效且选择性地抑制EGFR-TKI敏感突变和EGFR T790M。此前曾利用AURA和AURA2数据（晚期非小细胞肺癌[NSCLC]）报告过奥希替尼的群体药代动力学（popPK）模型。我们报告了纳入AURA3和FLAURA数据（晚期NSCLC）的更新后的popPK模型；模型验证使用了ADAURA数据（IB-IIIA期切除的NSCLC）。更新后的popPK分析基于来自AURA（n = 599）、AURA2（n = 210）、AURA3（n = 277）和FLAURA（n = 278）的患者，采用线性单室处置模型来描述奥希替尼及其代谢物AZ5104，并具有一级口服吸收。使用蒙特卡洛模拟开发了一个完整的协变量模型，以评估协变量对奥希替尼和AZ5104清除率的影响。使用ADAURA研究数据（n = 325）进行了外部验证。在最终的popPK模型中，奥希替尼（14.3 L/h；918 L）和AZ5104（31.3 L/h；143 L）的表观清除率和分布容积与先前的分析结果相当。白蛋白水平和体重影响奥希替尼的药代动力学，但这些影响在临床上不被认为有意义；其他协变量对药代动力学没有影响。拟合优度图表明该模型充分描述了所有数据。直观预测检查表明最终模型验证了奥希替尼辅助治疗的稳态药代动力学。PopPK模型表明，对于患者的年龄、性别、体重、种族、吸烟状况或治疗线，不需要调整奥希替尼剂量，证实了每天一次固定80 mg剂量对奥希替尼是最佳的。
