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Molecular Pharmacodynamics-Guided Scheduling of Biologically Effective Doses: A Drug Development Paradigm Applied to MET Tyrosine Kinase Inhibitors
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-02-14 , DOI: 10.1158/1535-7163.mct-17-0552
Apurva K Srivastava 1 , Melinda G Hollingshead 2 , Jeevan Prasaad Govindharajulu 1 , Joseph M Covey 3 , Dane Liston 3 , Melanie A Simpson 1 , James O Peggins 3 , Donald P Bottaro 4 , John J Wright 3 , Robert J Kinders 1 , James H Doroshow 3, 5 , Ralph E Parchment 1
Affiliation  

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 pY1234/1235MET/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 MET-amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pY1234/1235MET/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. Mol Cancer Ther; 17(3); 698–709. ©2018 AACR.

中文翻译:


分子药效学指导的生物有效剂量安排:应用于 MET 酪氨酸激酶抑制剂的药物开发范式



分子靶向药物的开发受益于使用药效学标记来识别低于 MTD 的“生物有效剂量”(BED),但在选择剂量方案和比较一类靶向药物的有效性时,这一知识仍未得到充分利用。我们试图为这种基于药效学的 BED 方案建立临床前概念验证,并使用 MET 激酶小分子抑制剂进行有效性比较。在类似 0 期的临床前环境中,利用 MET 信号传导的药效生物标志物测量(肿瘤 pY1234/1235MET/总 MET 比率),我们为几种 MET 激酶抑制剂开发了最佳剂量方案,并比较了它们在 MET 扩增的胃癌异种移植模型中的抗肿瘤功效(SNU-5)。使用可耐受剂量的 EMD1214063/MSC2156119J (tepotinib)、XL184 (cabozantinib) 和 XL880/GSK1363089 (foretinib) 可将肿瘤 pY1234/1235MET/总 MET 降低 95%–99%,但 ARQ197 (tivantinib) 则不行。不改变药效生物标志物。激酶抑制的持续时间和激酶恢复率因每种药物而异,强调开发定制剂量方案的重要性,以实现药效生物标志物持续抑制在所需水平(此处,≥90% MET 激酶抑制)。每种抑制剂的定制剂量方案产生了实质性且持续的肿瘤消退;达到相同水平的连续分子目标控制的定制剂量方案的等效效果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。 药效学指导的生物有效剂量方案(PD-BEDR)可能为药代动力学指导(例如替代组织中的药物浓度)提供更好的替代方案,用于开发和进行靶向药物的头对头比较。摩尔癌症治疗; 17(3); 698–709。 ©2018 AACR。
更新日期:2018-02-14
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