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Development of a minimal physiologically-based pharmacokinetic/pharmacodynamic model to characterize target cell depletion and cytokine release for T cell-redirecting bispecific agents in humans.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-02-10 , DOI: 10.1016/j.ejps.2020.105260
Xiling Jiang 1 , Xi Chen 1 , Pharavee Jaiprasart 1 , Thomas J Carpenter 1 , Rebecca Zhou 2 , Weirong Wang 1
Affiliation  

T cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 µg/m2/day stepwise dosing regimen comparing to a 60 µg/m2/day flat dose in NHL patients. Furthermore, by only modifying the system parameters specific for ALL patients, the mPBPK/PD model successfully predicted the mitigation of IL-6 release by a blinatumomab 5-15 µg/m2/day stepwise dosing regimen comparing to a 15 µg/m2/day flat dose. Our work provided a case example to show how mPBPK/PD model can be used to support the discovery and clinical development of T cell-redirecting bsAbs.

中文翻译:

建立最小的基于生理学的药代动力学/药效学模型,以表征人类T细胞重定向双特异性药物的靶细胞耗竭和细胞因子释放。

T细胞重定向双特异性抗体(bsAbs)是高效杀伤肿瘤的分子。在bsAb介导与靶细胞的结合之后,T细胞被激活并杀死靶细胞,同时诱导细胞因子释放,其水平升高可能导致威胁生命的细胞因子释放综合征(CRS)。临床证据表明,可以通过实施逐步给药策略来缓解CRS。在这里,我们使用报告的blinatumomab的临床前和临床数据,开发了一种基于机理的,基于最小生理学的药代动力学/药效学(mPBPK / PD)模型。mPBPK / PD模型可以合理地捕获非霍奇金病患者血液和各种作用部位(即红骨髓血管周围小生境,脾脏和淋巴结)的blinatumomab PK和B细胞耗竭情况 淋巴瘤(NHL)和急性淋巴细胞白血病(ALL)。以白介素6(IL-6)为例,我们的模型定量定量了blinatumomab 5-15-60 µg / m2 /天的逐步给药方案与NHL中60 µg / m2 / day固定剂量给药相比减轻细胞因子释放的特征。耐心。此外,通过仅修改ALL患者特有的系统参数,mPBPK / PD模型成功预测了blinatumomab 5-15 µg / m2 /天的逐步给药方案与15 µg / m2 /天的blinatumomab缓解了IL-6释放统一剂量。我们的工作提供了一个案例示例,展示了如何使用mPBPK / PD模型来支持T细胞重定向bsAb的发现和临床开发。我们的模型定量定量了5-15-60 µg / m2 /天的blinatumomab逐步给药方案与NHL患者的60 µg / m2 /天的固定剂量相比,减轻了细胞因子的释放。此外,通过仅修改ALL患者特有的系统参数,mPBPK / PD模型成功预测了blinatumomab 5-15 µg / m2 /天的逐步给药方案与15 µg / m2 /天的blinatumomab缓解了IL-6释放统一剂量。我们的工作提供了一个案例实例,展示了如何使用mPBPK / PD模型来支持T细胞重定向bsAb的发现和临床开发。我们的模型定量定量了5-15-60 µg / m2 /天的blinatumomab逐步给药方案与NHL患者的60 µg / m2 /天的固定剂量相比,减轻了细胞因子的释放。此外,通过仅修改ALL患者特有的系统参数,mPBPK / PD模型成功预测了blinatumomab 5-15 µg / m2 /天的逐步给药方案与15 µg / m2 /天的blinatumomab缓解了IL-6释放统一剂量。我们的工作提供了一个案例实例,展示了如何使用mPBPK / PD模型来支持T细胞重定向bsAb的发现和临床开发。mPBPK / PD模型成功预测了blinatumomab 5-15 µg / m2 /天的逐步给药方案与15 µg / m2 /天的固定剂量相比,IL-6释放的减轻。我们的工作提供了一个案例实例,展示了如何使用mPBPK / PD模型来支持T细胞重定向bsAb的发现和临床开发。mPBPK / PD模型成功预测了blinatumomab 5-15 µg / m2 /天的逐步给药方案与15 µg / m2 /天的固定剂量相比,IL-6释放的减轻。我们的工作提供了一个案例实例,展示了如何使用mPBPK / PD模型来支持T细胞重定向bsAb的发现和临床开发。
更新日期:2020-02-10
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