Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck.
Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck.
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DOI：
10.3892/ijo.30.4.927
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发表时间：
2007-04
影响因子：
5.2
通讯作者：
A. Sauter;C. Kloft;S. Gronau;F. Bogeschdorfer;T. Erhardt;W. Golze;C. Schroen;A. Staab;H. Riechelmann;K. Hoermann
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文献类型：
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作者：
A. Sauter;C. Kloft;S. Gronau;F. Bogeschdorfer;T. Erhardt;W. Golze;C. Schroen;A. Staab;H. Riechelmann;K. Hoermann
前药bivatuzumab mertansine （BIWI 1）是一种新的靶向cd44v6的人源化单克隆抗体，偶联于毒素mertansine。在一项I期剂量递增试验中，31名头颈部鳞状细胞癌患者接受25-325 mg/m2剂量的30分钟输注治疗。13例患者在3周后接受第二次输注。连续采集血清样本，测定前药BIWI - 1和解偶联BIWI - 1的药动学参数以及抗BIWI - 1抗体的发生情况。由于皮肤毒性，最大耐受剂量为300 mg/m2。在所有患者中未观察到免疫反应。对于BIWI 1和去偶联BIWI 1，清除率低且分布有限，导致3周后单次给药和重复给药的半衰期分别约为3-3.5天和6-7天。总体而言，药代动力学参数的个体间变异性较低。总的来说，两种化合物在单次和重复给药后的药代动力学在整个剂量范围内具有可比性，并且没有显著的积累发生。在所调查的剂量范围内，观察到BIWI - 1和去偶联BIWI - 1暴露的剂量成比例增加。根据体型（体重或体表面积）进行个体化剂量被认为是合适的，并被推荐用于新型免疫偶联物。
The prodrug bivatuzumab mertansine (BIWI 1) is a novel CD44v6-targeting humanized monoclonal antibody coupled to the toxin mertansine. In a phase I dose escalation trial 31 patients with squamous cell carcinomas of the head and neck were treated with doses of 25-325 mg/m2 as a 30-min infusion. Thirteen patients received a second infusion after 3 weeks. Serial serum samples were collected to determine the pharmacokinetic parameters of the prodrug BIWI 1 and of deconjugated BIWI 1 as well as the occurrence of anti-BIWI 1 antibodies. The maximum tolerated dose was reached at 300 mg/m2 attributable to skin toxicity. No immune response was observed in any patient. For BIWI 1 and deconjugated BIWI 1, clearance values were low and distribution was limited resulting in half-lives of approximately 3-3.5 days and approximately 6-7 days, respectively, for single and repeated dosing after three weeks. Overall, interindividual variability of the pharmacokinetic parameters was low. In general, the pharmacokinetics of both compounds after single and repeated dosing was comparable across the entire dose range and no significant accumulation took place. Over the dose range investigated, a dose proportional increase in the exposure of BIWI 1 and deconjugated BIWI 1 was observed. Dose individualization according to body size (weight or body surface area) was found to be appropriate and is recommended for the novel immunoconjugate.