Pharmacokinetic modeling of radiolabeled antibody distribution in man.

A Rescigno, H Bushe, A B Brill, M Rusckowski, T W Griffin, D J Hnatowich
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Abstract

This paper describes a method for the interpretation of the pharmacokinetics in cancer patients of an anti-CEA monoclonal antibody labeled with 111In. To determine the fate of the radiolabeled antibody administered i.v. to ten colon patients, the radioactivity contained in liver, spleen, kidneys, bone marrow, and tumor was measured and serum samples were counted. In addition each serum and urine sample was also analyzed by HPLC. The labeled antibody and two other radioactive species were observed in serum: an immunocomplex and a catabolic product. The computer program SAAM was used to fit the data. Thus, the rate constants for a number of pharmacokinetic models were calculated using the time-dependent serum radioactivity curves for each of the three species and the time-dependent radioactivity contained in normal organs. We also computed the model parameters for different connections between different organs, and using noncompartmental methods, the transit time, permanence time, and yield of those organs. Our results suggest that the immunocomplexes are formed in the circulation between circulating antibody and antigen, and that the rate of uptake by the liver depends on the concentration of the antibody in blood and not of the immunocomplex. Following deposition in the liver, free antibody does not appear to reenter the circulation, but once there it is catabolized. All breakdown products are then cleared into urine via serum.

放射性标记抗体在人体内分布的药代动力学模型。
本文介绍了一种用111In标记的抗cea单克隆抗体在癌症患者体内的药代动力学解释方法。为了确定10例结肠患者静脉注射放射性标记抗体的命运,测定了肝、脾、肾、骨髓和肿瘤中所含的放射性,并对血清样本进行了计数。此外,每个血清和尿液样本也进行HPLC分析。在血清中观察到标记抗体和其他两种放射性物质:免疫复合物和分解代谢产物。采用计算机程序SAAM对数据进行拟合。因此,许多药代动力学模型的速率常数是使用三种药物的随时间血清放射性曲线和正常器官中含的随时间放射性来计算的。我们还计算了不同器官之间不同连接的模型参数,并使用非隔室方法计算了这些器官的传递时间、永久时间和产量。我们的结果表明,免疫复合物是在循环抗体和抗原之间的循环中形成的,肝脏的摄取速率取决于血液中抗体的浓度,而不是免疫复合物的浓度。游离抗体在肝脏中沉积后,似乎不会再进入血液循环,但一旦进入循环就会被分解代谢。所有的分解产物通过血清进入尿液。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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