Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Cancer Chemother Pharmacol. 2012 May;69(5):1229-40. doi: 10.1007/s00280-011-1817-3. Epub 2012 Jan 20.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.
Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.
PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.
The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.
曲妥珠单抗-美坦新偶联物（T-DM1）是一种抗体药物偶联物，由曲妥珠单抗和 DM1 组成，DM1 是一种微管聚合抑制剂，通过稳定的硫醚键连接物共价结合。为了描述人表皮生长因子受体 2（HER2）阳性转移性乳腺癌患者中单用 T-DM1 的药代动力学（PK）特征，汇总了四项研究（TDM3569g、TDM4258g、TDM4374g 和 TDM4688g）的数据，这些研究中 T-DM1 的给药剂量为 3.6mg/kg，每 3 周（q3w）给药 1 次。
采用酶联免疫吸附试验或液相色谱串联质谱法，对多种分析物（T-DM1、总曲妥珠单抗（TT）、DM1 和关键代谢物）进行定量。采用标准非房室模型方法计算 T-DM1、TT 和 DM1 暴露的 PK 参数，并与疗效（客观缓解率）和安全性（血小板计数、肝转氨酶浓度）相关联。采用经验证的桥接抗体电化学发光或酶联免疫吸附试验，在重复给药后测量抗治疗性抗体（ATA）对 T-DM1 的免疫原性。
在第 1 周期和稳态时，各研究间 T-DM1、TT 和 DM1 的 PK 参数是一致的。T-DM1 PK 不受既往治疗中残留的曲妥珠单抗或循环的 HER2 细胞外结构域的影响。T-DM1 暴露与疗效、血小板减少症或转氨酶浓度升高之间未观察到显著相关性。在这四项研究中，在接受 T-DM1 q3w 治疗的 286 例可评价患者中，有 4.5%（13/286）检测到 ATA 形成。
单药 T-DM1（3.6mg/kg q3w）的 PK 特征可预测，特征明确，不受循环 HER2 细胞外结构域或残留曲妥珠单抗的影响。T-DM1 暴露与临床反应或主要不良事件无关。
