Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
Certara, Princeton, New Jersey, USA.
CPT Pharmacometrics Syst Pharmacol. 2020 Dec;9(12):718-730. doi: 10.1002/psp4.12569.
Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase II study (ALK in Lung Cancer Trial of AP26113 (ALTA)). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modeling using daily time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range, 30 mg once daily (q.d.) to 240 mg q.d.) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥ 2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d.
布加替尼是一种激酶抑制剂，适用于在克唑替尼治疗后进展或不耐受的间变性淋巴瘤激酶阳性的局部晚期或转移性非小细胞肺癌患者。该批准基于一项随机、剂量范围的 II 期研究（ALK in Lung Cancer Trial of AP26113 (ALTA)）的结果。尽管在 ALTA 中，疗效与剂量呈明显的相关性，但使用基于平均暴露时间的静态模型无法确定暴露-反应关系。然而，使用每日时间变化的浓度曲线下面积作为时间事件模型中的预测因子进行暴露-反应建模，预测增加布加替尼的剂量（范围：每日一次 30mg 至 240mg）将导致无进展生存期（PFS）、颅内无进展生存期和总生存期的临床意义上的改善。预测 2 级及以上皮疹和淀粉酶升高与布加替尼暴露显著相关。这些结果支持批准的治疗方案（每日 180mg 剂量，用 90mg 进行 7 天导入期）与每日 90mg 剂量相比，具有良好的获益-风险特征。
