U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
J Pharm Sci. 2019 Jan;108(1):692-700. doi: 10.1016/j.xphs.2018.10.064. Epub 2018 Nov 10.
Time-varying clearance (CL) has been recently recognized in U.S. Food and Drug Administration drug labels for oncology monoclonal antibodies. Pembrolizumab population CL at steady state decreased about 20% from the first dose, and individual CL changes varied from 75% decrease to 25% increase, which were correlating with disease conditions. From mechanism of action perspective, this research explored the longitudinal covariate effect on pembrolizumab CL based on data from a phase II/III clinical trial in patients with non-small cell lung cancer. Time courses of sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase were first characterized separately, and the post hoc parameters of each individual patient were fixed in the subsequent semimechanistically based modeling analysis. Pembrolizumab time-varying CL was assumed to be associated with the patient's sum of the longest tumor dimensions, lymphocyte count, albumin, and lactate dehydrogenase, and tumor-related pembrolizumab CL was assumed to be a fraction of total pembrolizumab CL in the semimechanistically based modeling.
最近，美国食品和药物管理局（FDA）在肿瘤单克隆抗体的药品标签中加入了时变清除率（CL）的信息。在稳态下，帕博利珠单抗的群体 CL 从第一剂开始下降了约 20%，个体 CL 的变化范围从下降 75%到增加 25%不等，这与疾病状况有关。从作用机制的角度来看，这项研究基于 II/III 期临床试验中非小细胞肺癌患者的数据，探索了纵向协变量对帕博利珠单抗 CL 的影响。首先分别描述了最长肿瘤尺寸、淋巴细胞计数、白蛋白和乳酸脱氢酶的时间过程，随后在后续基于半机械的建模分析中固定了每位患者的事后参数。假设帕博利珠单抗的时变 CL 与患者的最长肿瘤尺寸、淋巴细胞计数、白蛋白和乳酸脱氢酶的总和有关，而肿瘤相关的帕博利珠单抗 CL 则被假定为基于半机械的建模中总帕博利珠单抗 CL 的一部分。
