Tocilizumab Dosing for Management of T Cell-Engaging Bispecific Antibody-Related CRS in Patients With R/R B-Cell NHL

IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Candice Jamois, David C. Turner, Leonid Gibiansky, Feifei Li, Jean-Francois Menuet, Leonardo Roque Pereira, Linda Lundberg, Elena Guerini, David J. Carlile, James Relf, Michael C. Wei, Antonia Kwan, Nicolas Frey, Susan Grange
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Abstract

The recent surge in T-cell-engaging and chimeric antigen receptor (CAR) T-cell therapies is changing the landscape of cancer therapy. Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome that is a well-known complication of these therapies, of which interleukin-6 (IL-6) is a key mediator. Tocilizumab, an IL-6 receptor (IL-6R) antagonist, is approved for the management of CAR T-cell therapy-induced CRS in adults and in pediatric patients aged ≥ 2 years old. However, the approved dosing schedule was not based on IL-6R occupancy and may not be the most suitable schedule for T-cell-engaging therapies such as bispecific antibodies (bsAb) due to key differences in the levels of released IL-6, the clinical symptomatology of CRS, and the pharmacology of tocilizumab across settings. In this study, we adapted a previously developed tocilizumab and soluble IL-6R (sIL-6R) population pharmacokinetic model to describe and predict tocilizumab concentrations and sIL-6R occupancy over time in patients with anti-CD20 bsAb-induced CRS following tocilizumab dosing. Using this model, which incorporates target binding and receptor occupancy, we propose a new tocilizumab dosing regimen that is based on quantitative clinical pharmacology, cytokine analyses, and clinical practice patterns in patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) treated with the anti-CD20 bsAb mosunetuzumab or glofitamab. This schedule (up to two 8 mg/kg intravenous tocilizumab doses per CRS event at least 8 hours apart and a maximum of three doses in 6 weeks) can be used to effectively manage acute CRS induced by anti-CD20 bsAb in patients with R/R B-NHL.

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托珠单抗治疗R/R b细胞NHL患者T细胞结合双特异性抗体相关的CRS
最近t细胞结合和嵌合抗原受体(CAR) t细胞疗法的激增正在改变癌症治疗的前景。细胞因子释放综合征(CRS)是一种全身性炎症反应综合征,是这些治疗的一个众所周知的并发症,其中白细胞介素-6 (IL-6)是一个关键的中介。Tocilizumab是一种IL-6受体(IL-6R)拮抗剂,被批准用于治疗成人和2岁以上儿童患者的CAR - t细胞治疗诱导的CRS。然而,由于释放的IL-6水平、CRS的临床症状和tocilizumab的药理学差异,批准的给药方案并不是基于IL-6R的占用,并且可能不是最适合t细胞参与疗法(如双特异性抗体(bsAb))的方案。在这项研究中,我们采用了先前开发的托珠单抗和可溶性IL-6R (sIL-6R)群体药代动力学模型来描述和预测托珠单抗给药后抗cd20 bsab诱导的CRS患者的托珠单抗浓度和sIL-6R占用时间。利用这个结合靶标结合和受体占据的模型,我们提出了一种新的托珠单抗给药方案,该方案基于定量临床药理学、细胞因子分析和复发/难治性b细胞非霍奇金淋巴瘤(R/R B-NHL)患者使用抗cd20 bsAb mosunetuzumab或glofitamab治疗的临床实践模式。该方案(每次CRS事件最多2次8mg /kg静脉注射tocilizumab,间隔至少8小时,6周内最多3次)可用于有效管理R/R B-NHL患者抗cd20 bsAb诱导的急性CRS。
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来源期刊
CiteScore
12.70
自引率
7.50%
发文量
290
审稿时长
2 months
期刊介绍: Clinical Pharmacology & Therapeutics (CPT) is the authoritative cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy, and evaluation of therapeutics. CPT welcomes original Articles in the emerging areas of translational, predictive and personalized medicine; new therapeutic modalities including gene and cell therapies; pharmacogenomics, proteomics and metabolomics; bioinformation and applied systems biology complementing areas of pharmacokinetics and pharmacodynamics, human investigation and clinical trials, pharmacovigilence, pharmacoepidemiology, pharmacometrics, and population pharmacology.
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