Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Biological Testing Branch, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Mol Cancer Ther. 2018 Mar;17(3):698-709. doi: 10.1158/1535-7163.MCT-17-0552. Epub 2018 Feb 14.
The development of molecularly targeted agents has benefited from use of pharmacodynamic markers to identify "biologically effective doses" (BED) below MTDs, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such pharmacodynamics-based BED regimens and effectiveness comparisons using MET kinase small-molecule inhibitors. Utilizing pharmacodynamic biomarker measurements of MET signaling (tumor pYMET/total MET ratio) in a phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a -amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pYMET/total MET of 95%-99% were achievable with tolerable doses of EMD1214063/MSC2156119J (tepotinib), XL184 (cabozantinib), and XL880/GSK1363089 (foretinib), but not ARQ197 (tivantinib), which did not alter the pharmacodynamic biomarker. Duration of kinase suppression and rate of kinase recovery were specific to each agent, emphasizing the importance of developing customized dosage regimens to achieve continuous suppression of the pharmacodynamic biomarker at the required level (here, ≥90% MET kinase suppression). The customized dosage regimen of each inhibitor yielded substantial and sustained tumor regression; the equivalent effectiveness of customized dosage regimens that achieve the same level of continuous molecular target control represents preclinical proof-of-concept and illustrates the importance of proper scheduling of targeted agent BEDs. Pharmacodynamics-guided biologically effective dosage regimens (PD-BEDR) potentially offer a superior alternative to pharmacokinetic guidance (e.g., drug concentrations in surrogate tissues) for developing and making head-to-head comparisons of targeted agents. .
分子靶向药物的发展得益于使用药效动力学标志物来确定低于最大耐受剂量 (MTD) 的“生物有效剂量” (BED)，但在选择剂量方案和比较同类靶向药物的有效性方面，这方面的知识仍未得到充分利用。我们试图利用 MET 激酶小分子抑制剂为这种基于药效动力学的 BED 方案和有效性比较建立临床前概念验证。在类似于 0 期临床试验的临床前环境中，利用 MET 信号转导的药效动力学生物标志物测量（肿瘤 pYMET/总 MET 比值），我们为几种 MET 激酶抑制剂开发了最佳剂量方案，并在一个扩增的胃癌异种移植模型（SNU-5）中比较了它们的抗肿瘤疗效。用可耐受剂量的 EMD1214063/MSC2156119J（ tepotinib）、XL184（cabozantinib）和 XL880/GSK1363089（foretinib）可实现 95%-99%的肿瘤 pYMET/总 MET 降低，但 ARQ197（tivantinib）则不行，其不会改变药效动力学生物标志物。激酶抑制的持续时间和激酶恢复的速率因每种药物而异，这强调了开发定制剂量方案以在所需水平（这里为≥90% MET 激酶抑制）持续抑制药效动力学生物标志物的重要性。每种抑制剂的定制剂量方案都产生了显著且持续的肿瘤消退；实现相同水平的连续分子靶标控制的定制剂量方案的等效有效性代表了临床前概念验证，并说明了正确安排靶向药物 BED 的重要性。药效动力学指导的生物有效剂量方案（PD-BEDR）可能为开发和比较靶向药物提供优于药代动力学指导（例如，替代组织中的药物浓度）的替代方案。
