BioPharmaceuticals R&D, Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge, UK.
Formerly BioPharmaceuticals R&D, Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge, UK.
AAPS J. 2021 Mar 17;23(3):46. doi: 10.1208/s12248-021-00573-1.
Savolitinib is an oral, potent, and highly selective MET-tyrosine kinase inhibitor under investigation in various tumor types. A thorough QT study evaluated effects on QT interval after a 600-mg single savolitinib dose in healthy subjects. We report exposure-response (E-R) modeling from this study to characterize the effects of savolitinib and its metabolites, M2 and M3, on QTc changes. In a novel application, in vitro potencies against hERG current provided mechanistic support to model the metabolites' effects. The hERG IC50 estimates (95% CI) were 25.8 (22.2-29.9) and 22.6 (14.7-34.6) μM for parent and M2, respectively. The E-R was described by both linear and E models, with exposure captured by an active moiety that consisted of savolitinib and M2 concentrations, weighted by the hERG IC50 ratio (1.14). The maximal increase in ΔΔQTcF and EC50 estimates (95% CI) was 18.5 (9.2-27.7) ms and 5709 (2889-8529) nM, respectively. Ignoring M2 contribution resulted in under prediction of QTcF prolongation in the hypothetical case of inhibited M2 clearance; at 300 mg C, the mean (90% CI) of ∆∆QTcF was 9.0 (5.7-12.6) and 5.9 (2.9-8.9) ms using the hERG-informed and parent-only linear models, respectively. Simulations in normal setting confirmed modest QTcF prolongation with 600 mg, but not 300 mg. Using the linear model, the mean (90% CI) maximum ΔΔQTcF were 12.3 (8.6-16.2) and 5.5 (2.6-8.5) ms for 600 and 300 mg, respectively. Further clinical studies will monitor cardiac safety to assess the clinical significance of QT-interval prolongation with savolitinib.
索凡替尼是一种口服、强效和高度选择性的 MET 酪氨酸激酶抑制剂，目前正在多种肿瘤类型中进行研究。一项全面的 QT 研究评估了健康受试者单次服用 600 毫克索凡替尼后对 QT 间期的影响。我们报告了这项研究中的暴露-反应 (E-R) 建模结果，以描述索凡替尼及其代谢物 M2 和 M3 对 QTc 变化的影响。在一个新颖的应用中，针对 hERG 电流的体外效力为模型代谢物的作用提供了机制支持。hERG IC50 估计值（95%CI）分别为 25.8（22.2-29.9）和 22.6（14.7-34.6）μM 用于母体和 M2。E-R 由线性和 E 模型描述，通过包含索凡替尼和 M2 浓度的活性部分来描述暴露，该活性部分的权重由 hERG IC50 比值（1.14）决定。ΔΔQTcF 的最大增加和 EC50 估计值（95%CI）分别为 18.5（9.2-27.7）ms 和 5709（2889-8529）nM。忽略 M2 贡献会导致在假设的 M2 清除受到抑制的情况下对 QTcF 延长的预测不足；在 300mgC 时，使用 hERG 知情和仅母体线性模型，Δ∆QTcF 的平均值（90%CI）分别为 9.0（5.7-12.6）和 5.9（2.9-8.9）ms。在正常情况下的模拟证实了 600mg 剂量会适度延长 QTcF，但 300mg 剂量则不会。使用线性模型，600mg 和 300mg 的平均（90%CI）最大ΔΔQTcF 分别为 12.3（8.6-16.2）和 5.5（2.6-8.5）ms。进一步的临床研究将监测心脏安全性，以评估索凡替尼引起的 QT 间期延长的临床意义。
