Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
J Nucl Med. 2016 Apr;57(4):594-600. doi: 10.2967/jnumed.115.167825. Epub 2016 Jan 14.
A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them.
The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the β-emitters (188)Re, (177)Lu, and (90)Y and the α-emitters (211)At, (213)Bi, and (212)Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated.
According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of α- and β-emitters bound to mAbs were compared. For α-emitters, microtumors receive high doses (>20 Gy or 100 Sv [relative biological effect = 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For β-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived (90)Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies.
According to the presented model, α-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors.
构建生物动力学模型以评估和优化用于微转移瘤的各种腹腔内放射性免疫疗法。该模型用于计算预期的微肿瘤和关键健康器官的吸收剂量，并展示了如何优化腹腔内靶向放疗以最大化它们之间的比值。
使用软件包对负责腹腔内输注放射性标记单克隆抗体（mAb）的各种转运机制进行建模。使用文献中的数据补充了从我们的临床 I 期研究中得出的药代动力学数据以设置参数值。比较了β发射体（188）Re、（177）Lu 和（90）Y 和α发射体（211）At、（213）Bi 和（212）Pb 的结果。研究了提高比活度、通过引入渗透剂延长停留时间以及改变输注剂的活性浓度的效果。
根据模型，由于淋巴引流，1.7 L 输注生理盐水的体积将减少 0.3 mL/min，由于跨毛细血管对流成分，体积将减少 0.7 mL/min。渗透剂的添加可降低骨髓的辐射剂量。比较了与 mAb 结合的α和β发射器的临床相关放射性浓度。对于α发射器，微肿瘤接受高剂量（>20 Gy 或 100 Sv[相对生物效应=5]）。由于大部分肿瘤剂量来自细胞结合的放射性核素，因此比活度的增加将进一步增加肿瘤剂量，而不会影响腹膜液或骨髓的剂量。对于β发射器，肿瘤将接受几乎完全非特异性照射。相比之下，细胞结合的放射性标记 mAb 的剂量可以忽略不计。对于长寿命的（90）Y，在临床研究中给予的最大活性浓度下，预计肿瘤剂量较低。
根据提出的模型，需要α发射器来实现足以消除微肿瘤的辐射剂量。
