Loh A, Sgouros G, O'Donoghue J A, Deland D, Puri D, Capitelli P, Humm J L, Larson S M, Old L J, Divgi C R
Department of Medical Physics, Nuclear Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Nucl Med. 1998 Mar;39(3):484-9.
A model that describes the pharmacokinetic distribution of 131I-labeled G250 antibody is developed.
Previously collected pharmacokinetic data from a Phase I-II study of 131I-G250 murine antibody against renal cell carcinoma were used to develop a mathematical model describing antibody clearance from serum and the whole body. Survey meter measurements, obtained while the patient was under radiation precautions, and imaging data, obtained at later times, were combined to evaluate whole-body clearance kinetics over an extended period.
A linear two-compartment model was found to provide good fits to the data. The antibody was injected into Compartment 1, the initial distribution volume (Vd) of the antibody, which included serum. The antibody exchanged with the rest of the body, Compartment 2, and was eventually excreted. Data from 13 of the 16 patients fit the model with unique parameters; the maximum, median and minimum values for model-derived Vd were 6.3, 3.7 and 2.11, respectively. The maximum, median and minimum values for the excretion rate were 8 x 10(-2), 2.4 x 10(-2) and 1.3 x 10(-2) hr(-1), respectively. Parameter sensitivity analysis showed that a change in the transfer rate constant from serum to the rest of the body had the greatest effect on serum cumulative activity and that the rate constant for excretion had the greatest effect on whole-body cumulative activity.
A linear two-compartment model was adequate in describing the serum and whole-body kinetics of G250 antibody distribution. The median initial distribution volume predicted by the model was consistent with the nominal value of 3.81. A wide variability in fitted parameters was observed among patients, reflecting the differences in individual patient clearance and exchange kinetics of G250 antibody. By selecting median parameter values, such a model may be used to evaluate and design prolonged multiple administration radioimmunotherapy protocols.
建立了一个描述¹³¹I标记的G250抗体药代动力学分布的模型。
使用先前在一项针对肾细胞癌的¹³¹I - G250鼠源抗体的I - II期研究中收集的药代动力学数据，建立一个描述抗体从血清和全身清除的数学模型。将患者在辐射防护措施下获得的剂量仪测量值和稍后时间获得的成像数据相结合，以评估延长时间段内的全身清除动力学。
发现线性二室模型能很好地拟合数据。抗体注入第1室，即抗体的初始分布容积（Vd），其中包括血清。抗体与身体的其余部分（第2室）进行交换，最终被排泄。16名患者中的13名的数据以独特的参数拟合该模型；模型推导的Vd的最大值、中位数和最小值分别为6.3、3.7和2.11。排泄率的最大值、中位数和最小值分别为8×10⁻²、2.4×10⁻²和1.3×10⁻² hr⁻¹。参数敏感性分析表明，从血清到身体其余部分的转运速率常数的变化对血清累积活性影响最大，而排泄速率常数对全身累积活性影响最大。
线性二室模型足以描述G250抗体分布的血清和全身动力学。该模型预测的初始分布容积中位数与标称值3.81一致。在患者中观察到拟合参数存在很大差异，反映了G250抗体个体患者清除和交换动力学的差异。通过选择中位数参数值，这样的模型可用于评估和设计延长的多次给药放射免疫治疗方案。
