First-In-Human for Biologics with Immunogenicity Assessment
要准确预测单克隆抗体（mAbs）、治疗性蛋白质和双/多特异性药物等生物制剂的首次人体试验（FIH）剂量，需要考虑决定此类制剂临床 PK 特性的各种特征，包括靶向介导的药物处置（TMDD）和抗药物抗体（ADAs）引起的免疫原性（IG）。此外，鉴于高活性生物治疗药物的出现，它们在低剂量时就会诱发严重的毒性反应，包括细胞因子释放综合征和神经毒性，因此，人们开始根据预期的生物效应而不是传统的临床前安全系数来使用 FIH 起始剂量。
Simcyp FIH 生物平台的设计考虑到了这些复杂的机制，利用我们独特的 QSP 平台，以现成的临床前输入数据为基础，进行可靠的 FIH 剂量预测。
这种方法整合了临床前机制性证据和生理系统模型，以研究和预测生物治疗药物的人体 PK。
Focus on Immunogenicity (IG)
As defined by the US FDA, IG is the propensity of a therapeutic product to generate immune responses to itself , or to induce certain immunologically related adverse clinical events. This can be exacerbated when administered as multiple doses over prolonged periods. Administration of biotherapeutics frequently triggers immunogenic responses in patients in the form of ADAs, which may affect PK and thus drug efficacy. The immunogenic response generally includes both (T cell) and (antibody) arms of the immune response.
Immunogenicity Risk Assessment Using Certara’s IG Simulator
Certara’s IG Risk Assessment product leverages the proprietary IG Simulator
to predict and manage IG in a specific development program, and guide design of potential novel molecules. The IG Simulator can not only predict IG incidence, but uniquely also the impact on PK and how this is influenced by the dosing regimen.
An initial IG Risk Assessment can be determined with very little data – the structure of the protein alone is all that is needed for a first in silico prediction. Additional in vitro and in vivo data can be integrated in subsequent steps. The IG Risk Assessment will guide critical decision-making around compound selection, human prediction and design of phase 1 studies.
