Department of Antibody Development, TRION Research GmbH, Am Klopferspitz 19, 82152 Martinsried, Germany.
Br J Clin Pharmacol. 2010 Jun;69(6):617-25. doi: 10.1111/j.1365-2125.2010.03635.x.
Catumaxomab is the first EMEA approved trifunctional anti-EpCAMxanti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development.
Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 microg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored.
Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml(-1) range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (C(max)) of 403 pg ml(-1). The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model.
Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate.
Catumaxomab 是首个获得 EMEA 批准的用于治疗恶性腹水癌症患者的三功能抗-EpCAMx 抗-CD3 抗体。进行了一项 II 期药代动力学研究，以确定局部和全身抗体浓度以及抗药物抗体 (ADA) 的发展。
13 名患有症状性恶性腹水的癌症患者接受了四个递增剂量的 10、20、50 和 150μg catumaxomab 腹腔内 (i.p.) 输注，分别在第 0、3、6 或 7 天和第 10 天输注。通过实施非临床小鼠肿瘤模型的支持性数据来研究 catumaxomab 的药代动力学。此外，还监测了 ADA 的发展情况。
13 名患者中有 10 名可进行药代动力学分析。在治疗过程中，catu- maxomab 在腹水中的浓度逐渐升高，达到了 ng ml(-1)范围内的有效浓度。即使在循环中停留数天后，catu- maxomab 仍然保持免疫活性。观察到的系统 catumaxomab 暴露量较低（<1%），最大中位数血浆浓度（C(max)）为 403pg ml(-1)。血浆中的平均消除半衰期为 2.13 天。所有患者均产生了 ADA，但不是在最后一次输注之前。在一个明确的小鼠肿瘤模型中，观察到的个体间变异性高和系统暴露量低可能与肿瘤负担、效应细胞数量和系统抗体生物利用度之间的反比关系有关。
基于高且有效的局部浓度、低的系统暴露量和可接受的安全性概况，我们证实了 catumaxomab 腹腔内应用方案治疗恶性腹水是合适的。
