Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Eur J Pharm Sci. 2023 Jul 1;186:106467. doi: 10.1016/j.ejps.2023.106467. Epub 2023 May 16.
Despite their use to treat cancers with specific genetic aberrations, targeted therapies elicit heterogeneous responses. Sources of variability are critical to targeted therapy drug development, yet there exists no method to discern their relative contribution to response heterogeneity.
We use HER2-amplified breast cancer and two agents, neratinib and lapatinib, to develop a platform for dissecting sources of variability in patient response. The platform comprises four components: pharmacokinetics, tumor burden and growth kinetics, clonal composition, and sensitivity to treatment. Pharmacokinetics are simulated using population models to capture variable systemic exposure. Tumor burden and growth kinetics are derived from clinical data comprising over 800,000 women. The fraction of sensitive and resistant tumor cells is informed by HER2 immunohistochemistry. Growth rate-corrected drug potency is used to predict response. We integrate these factors and simulate clinical outcomes for virtual patients. The relative contributions of these factors to response heterogeneity arecompared.
The platform was verified with clinical data, including response rate and progression-free survival (PFS). For both neratinib and lapatinib, the growth rate of resistant clones influenced PFS to a higher degree than systemic drug exposure. Variability in exposure at labeled doses did not significantly influence response. Sensitivity to drug strongly influenced responses to neratinib. Variability in patient HER2 immunohistochemistry scores influenced responses to lapatinib. Exploratory twice daily dosing improved PFS for neratinib but not lapatinib.
The platform can dissect sources of variability in response to target therapy, which may facilitate decision-making during drug development.
尽管针对具有特定遗传异常的癌症的靶向治疗具有疗效，但它们会引起异质性的反应。变异性的来源对于靶向治疗药物的开发至关重要，但目前还没有方法来辨别它们对反应异质性的相对贡献。
我们使用 HER2 扩增的乳腺癌和两种药物（奈拉替尼和拉帕替尼）来开发一个用于剖析患者反应中变异性来源的平台。该平台由四个部分组成：药代动力学、肿瘤负担和生长动力学、克隆组成和对治疗的敏感性。药代动力学使用群体模型进行模拟，以捕获系统暴露的可变性。肿瘤负担和生长动力学源自包含超过 80 万名女性的临床数据。敏感和耐药肿瘤细胞的比例由 HER2 免疫组织化学告知。校正后的生长速率药物效力用于预测反应。我们整合这些因素并模拟虚拟患者的临床结局。比较这些因素对反应异质性的相对贡献。
该平台通过包括应答率和无进展生存期（PFS）在内的临床数据进行了验证。对于奈拉替尼和拉帕替尼，耐药克隆的生长速率对 PFS 的影响程度高于系统药物暴露。标签剂量下暴露的可变性对反应没有显著影响。对药物的敏感性强烈影响了对奈拉替尼的反应。患者 HER2 免疫组织化学评分的变异性影响了对拉帕替尼的反应。探索性的每日两次给药改善了奈拉替尼的 PFS，但对拉帕替尼没有改善。
该平台可以剖析对靶向治疗反应的变异性来源，这可能有助于在药物开发过程中进行决策。
