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Semimechanistic Physiologically-Based Pharmacokinetic/Pharmacodynamic Model Informing Epcoritamab Dose Selection for Patients With B-Cell Lymphomas
Clinical Pharmacology & Therapeutics ( IF 6.7 ) Pub Date : 2022-08-23 , DOI: 10.1002/cpt.2729
Tommy Li 1 , Ida H Hiemstra 2 , Christopher Chiu 1 , Roberto S Oliveri 3 , Brian Elliott 1 , Dena DeMarco 1 , Theodora Salcedo 1 , Frederikke Lihme Egerod 3 , Kate Sasser 1 , Tahamtan Ahmadi 1 , Manish Gupta 1
Affiliation  

Epcoritamab is a CD3xCD20 bispecific antibody (bsAb) that induces T-cell–mediated cytotoxicity against CD20-positive B cells. Target engagement and crosslinking of CD3 and CD20 (trimer formation) leads to activation and expansion of T cells and killing of malignant B cells. The primary objective of the dose-escalation part of the phase I/II trial of epcoritamab was to determine the maximum tolerated dose, recommended phase II dose (RP2D), or both. For bsAbs, high target saturation can negatively affect trimer formation. The unique properties and mechanisms of action of bsAbs require novel pharmacokinetic (PK) modeling methods to predict clinical activity and inform RP2D selection. Traditional PK/pharmacodynamic (PD) modeling approaches are inappropriate because they may not adequately predict exposure–response relationships. We developed a semimechanistic, physiologically-based PK/PD model to quantitatively describe biodistribution, trimer formation, and tumor response using preclinical, clinical PK, biomarker, tumor, and response data from the dose-escalation part of the phase I/II trial. Clinical trial simulations were performed to predict trimer formation and tumor response in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Model-predicted trimer formation plateaued at doses of 48 to 96 mg. Simulation results suggest that the 48-mg dose may achieve optimal response rates in DLBCL and FL. Exposure–safety analyses showed a flat relationship between epcoritamab exposure and risk of cytokine release syndrome in the dose range evaluated. This novel PK/PD modeling approach guided selection of 48 mg as the RP2D and provides a framework that may be applied to other CD3 bsAbs.

中文翻译:

基于生理学的半机械药代动力学/药效学模型告知 B 细胞淋巴瘤患者的 Epcoritamab 剂量选择

Epcoritamab 是一种 CD3xCD20 双特异性抗体 (bsAb),可诱导 T 细胞介导的针对 CD20 阳性 B 细胞的细胞毒性。CD3 和 CD20 的靶向结合和交联(三聚体形成)导致 T 细胞的激活和扩增以及恶性 B 细胞的杀伤。epcoritamab I/II 期试验剂量递增部分的主要目标是确定最大耐受剂量、推荐的 II 期剂量 (RP2D) 或两者。对于 bsAb,高目标饱和度会对三聚体形成产生负面影响。bsAb 的独特特性和作用机制需要新的药代动力学 (PK) 建模方法来预测临床活性并为 RP2D 选择提供信息。传统的 PK/药效学 (PD) 建模方法是不合适的,因为它们可能无法充分预测暴露-反应关系。我们开发了一种半机械的、基于生理学的 PK/PD 模型,使用来自 I/II 期试验剂量递增部分的临床前、临床 PK、生物标志物、肿瘤和反应数据来定量描述生物分布、三聚体形成和肿瘤反应。进行临床试验模拟以预测弥漫性大 B 细胞淋巴瘤 (DLBCL) 或滤泡性淋巴瘤 (FL) 患者的三聚体形成和肿瘤反应。模型预测的三聚体形成在 48 至 96 毫克的剂量下趋于稳定。模拟结果表明,48 mg 剂量可在 DLBCL 和 FL 中实现最佳反应率。暴露-安全分析显示,在评估的剂量范围内,epcoritamab 暴露与细胞因子释放综合征风险之间呈平坦关系。
更新日期:2022-08-23
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