Mosunetuzumab (Mosun) 是一种 CD20xCD3 T 细胞接合双特异性抗体，可重定向 T 细胞以消除恶性 B 细胞。批准的 1/2/60/30mg IV 逐步剂量方案旨在减轻细胞因子释放综合征 (CRS) 并最大限度地提高早期周期的疗效。群体药代动力学 (popPK) 模型是根据 439 名接受 Mosun IV 单药治疗的复发/难治性 B 细胞非霍奇金淋巴瘤患者开发的，包括固定剂量（每 3 周 (q3w) 0.05-2.8mg IV）和第 1 周期递增给药组（0.4/1/2.8-1/2/60/30 mg IV q3w）。在 Mosun 治疗之前，约 50% 的患者残留有先前治疗中的抗 CD20 药物（例如利妥昔单抗或 obinutuzumab）。 CD20 受体结合动力学和利妥昔单抗/obinutuzumab PK 被纳入模型中，以计算随时间变化的 Mosun CD20 受体占据百分比 (RO%)。具有时间依赖性清除率 (CL) 的两室模型最好地描述了数据。典型患者的初始 CL 为 1.08L/天，过渡到稳态 CL 为 0.584L/天。 PK参数的统计相关协变量包括体重、白蛋白、性别、肿瘤负荷和基线抗CD20药物浓度；没有发现协变量对批准剂量的暴露具有临床相关影响。 Mosun CD20 RO% 变化很大，归因于残留基线抗 CD20 药物浓度的巨大变化（中位值=10μg/mL）。 60mg 负荷剂量增加了第 1 周期中 Mosun CD20 RO%，在存在竞争性抗 CD20 药物的情况下提供有效的暴露。 PopPK 模型模拟，调查 Mosun 剂量延迟，告知治疗恢复方案，以确保 CRS 缓解。© 2024 作者。 《临床和转化科学》由 Wiley periodicals LLC 代表美国临床药理学和治疗学会出版。

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.05-2.8 mg IV every 3 weeks (q3w)) and Cycle 1 step-up dosing groups (0.4/1/2.8-1/2/60/30 mg IV q3w). Prior to Mosun treatment, ~50% of patients had residual levels of anti-CD20 drugs (e.g., rituximab or obinutuzumab) from prior treatment. CD20 receptor binding dynamics and rituximab/obinutuzumab PK were incorporated into the model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. A two-compartment model with time-dependent clearance (CL) best described the data. The typical patient had an initial CL of 1.08 L/day, transitioning to a steady-state CL of 0.584 L/day. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline anti-CD20 drug concentration; no covariate was found to have a clinically relevant impact on exposure at the approved dose. Mosun CD20 RO% was highly variable, attributed to the large variability in residual baseline anti-CD20 drug concentration (median = 10 μg/mL). The 60 mg loading doses increased Mosun CD20 RO% in Cycle 1, providing efficacious exposures in the presence of the competing anti-CD20 drugs. PopPK model simulations, investigating Mosun dose delays, informed treatment resumption protocols to ensure CRS mitigation.© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.