Pharmacometric Applications and Challenges in the Development of Therapeutic Antibodies in Immuno-Oncology.
Pharmacometric Applications and Challenges in the Development of Therapeutic Antibodies in Immuno-Oncology.
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DOI：
10.1007/s40495-018-0142-5
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发表时间：
2018-08-01
影响因子：
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通讯作者：
Meibohm, Bernd
中科院分区：
文献类型：
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作者：
Diao, Lei;Meibohm, Bernd
回顾的目的：在过去的几年里，针对免疫刺激通路关键检查点的单克隆抗体已经成为癌症免疫治疗的主流。本文简要介绍了药物计量学和定量临床药理学方法在这些新型生物制剂开发中的应用及其关键影响。最近的研究发现：广泛应用药物计量学方法来表征主要疗效和安全性终点的暴露-反应关系，促进了免疫肿瘤学中单克隆抗体的临床开发和最佳剂量方案的选择。这些分析技术应用于抗CTLA-4抗体ipilimumab，以及抗PD1/PD-L1抗体nivolumab， pembrolizumab, avelumab， atezolizumab和durvalumab。定量临床药理学的使用，包括基于模型的分析，不仅支持确定具有可接受安全限制的有效剂量，而且还能够解决复杂的挑战，例如大多数化合物观察到的抗体清除率的时间和反应依赖性变化。摘要：药物计量学方法的广泛和系统应用为阐明、解释和整合临床前、生化和临床数据提供了关键方面，为开发安全有效的免疫肿瘤学单克隆抗体给药方案提供了支持，从而促进了这类有前景的新型生物制剂在未满足医疗需求的癌症患者中的临床应用。
PURPOSE OF REVIEW: Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immunotherapy. This article provides a brief review of the application and key impact of pharmacometrics and quantitative clinical pharmacology approaches in the development of these novel biologics.RECENT FINDINGS: The clinical development and selection of optimal dosing regimens for monoclonal antibodies used in immune-oncology has been facilitated by an extensive application of pharmacometric approaches to characterize the exposure-response relationship for major efficacy and safety endpoints. These analysis techniques were applied for the anti CTLA-4 antibody ipilimumab, as well as the anti PD1/PD-L1 antibodies nivolumab, pembrolizumab, avelumab, atezolizumab and durvalumab. The utilization of quantitative clinical pharmacology, including model-based analyses, did not only support the identification of efficacious doses with acceptable safety limits, but was also able to address complicating challenges such as time- and response-dependent changes in antibody clearance as observed for most compounds.SUMMARY: A widespread and systematic application of pharmacometric approaches has provided key aspects in elucidating, interpreting and integrating preclinical, biochemical and clinical data in support of the development of safe and efficacious dosing regimens of monoclonal antibodies used in immuno-oncology, thereby facilitating the clinical use of this promising new class of biologics in cancer patients with unmet medical needs.