Blinatumomab, a Bispecific T-cell Engager (BiTE®) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications
Blinatumomab, a Bispecific T-cell Engager (BiTE®) for CD-19 Targeted Cancer Immunotherapy: Clinical Pharmacology and Its Implications
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DOI：
10.1007/s40262-016-0405-4
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发表时间：
2016-10-01
影响因子：
4.5
通讯作者：
Doshi, Sameer
中科院分区：
文献类型：
--
作者：
Zhu, Min;Wu, Benjamin;Doshi, Sameer
背景和目的Blinatumomab是一种双特异性T细胞增殖剂（BiTE（R））抗体构建体，可瞬时连接CD 19阳性B细胞和CD 3阳性T细胞，导致诱导T细胞介导的B细胞系列裂解和伴随的T细胞增殖。Blinatumomab在临床试验中显示出抗白血病活性，并被美国食品药品监督管理局批准用于治疗费城染色体阴性复发性/难治性前体B细胞急性淋巴细胞白血病（r/r ALL）。这项工作的目的是表征blinatumomab的药代动力学和药效学，并评估dosing regimens.Methods数据来自6个I期和II期试验的患者与r/r ALL，微小残留疾病阳性ALL，非霍奇金淋巴瘤（NHL）进行了分析。Blinatumomab的药代动力学通过非房室和群体药代动力学分析进行表征，药效学用图表描述。结果Blinatumomab在5-90 μ g/m2/d剂量范围内连续静脉输注4-8周/周期时呈现线性药代动力学，无靶向介导的处置。分布容积、清除率和消除半衰期的估计平均值（标准差）分别为4.52（2.89）L、2.72（2.71）L/h和2.11（1.42）h。ALL和NHL患者的药代动力学相似，不受患者人口统计学的影响，支持成人的固定剂量。虽然肌酐清除率是药物清除率的重要协变量，但轻度或中度肾损害患者无需调整剂量。中和抗药抗体的发生率<1%。Blinatumomab的药效学特征为T细胞再分布和活化、B细胞耗竭和一过性剂量依赖性细胞因子升高。Blinatumomab并不直接影响细胞色素P450酶;细胞因子可能引发短暂的细胞色素P450抑制，诱导药物相互作用的可能性较低。结论Blinatumomab具有独特的药代动力学和免疫学特征，需要适应症依赖性给药方案。在高肿瘤负荷疾病中，需要逐步给药以达到足够的疗效并最大限度地减少细胞因子释放。
Background and Objectives Blinatumomab is a bispecific T-cell engager (BiTE (R)) antibody construct that transiently links CD19-positive B cells to CD3-positive T cells, resulting in induction of T-cell-mediated serial lysis of B cells and concomitant T-cell proliferation. Blinatumomab showed anti-leukemia activity in clinical trials and was approved by the US Food and Drug Administration for the treatment of Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r ALL). The objectives of this work were to characterize blinatumomab pharmacokinetics and pharmacodynamics and to evaluate dosing regimens.Methods Data from six phase I and II trials in patients with r/r ALL, minimal residual disease-positive ALL, and non-Hodgkin's lymphoma (NHL) were analyzed. Blinatumomab pharmacokinetics was characterized by non-compartmental and population pharmacokinetic analyses and pharmacodynamics was described graphically.Results Blinatumomab exhibited linear pharmacokinetics under continuous intravenous infusion for 4-8 weeks per cycle over a dose range of 5-90 mu g/m(2)/day, without target-mediated disposition. Estimated mean (standard deviation) volume of distribution, clearance, and elimination half-life were 4.52 (2.89) L, 2.72 (2.71) L/h, and 2.11 (1.42) h, respectively. Pharmacokinetics was similar in patients with ALL and NHL and was not affected by patient demographics, supporting fixed dosing in adults. Although creatinine clearance was a significant covariate of drug clearance, no dose adjustment was required in patients with mild or moderate renal impairment. Incidence of neutralizing antidrug antibodies was < 1 %. Blinatumomab pharmacodynamics featured T-cell redistribution and activation, B-cell depletion, and transient dose-dependent cytokine elevation. Blinatumomab did not affect cytochrome P450 enzymes directly; cytokines may trigger transient cytochrome P450 suppression with low potential for inducing drug interactions.Conclusions Blinatumomab has unique pharmacokinetic and immunological features that require indication-dependent dosing regimens. Stepped dosing is required to achieve adequate efficacy and minimize cytokine release in diseases with high tumor burden.