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药品详细

ado-trastuzumab emtansine(曲妥珠单抗注射液)

化学结构式图
中文名
曲妥珠单抗注射液
英文名
ado-trastuzumab emtansine
分子式
Not Available
化学名
分子量
Not Available
CAS号
1018448-65-
ATC分类
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Ado-trastuzumab emtansine, formerly called Trastuzumab-DM1 (T-DM1) as an investigational drug, is a first-in-class HER2 antibody drug conjugate (ADC) comprised of Genentech’s trastuzumab antibody linked to ImmunoGen’s cell-killing agent, DM1. T-DM1 combines two strategies— anti-HER2 activity and targeted intracellular delivery of the potent anti-microtubule agent, DM1 (a maytansine derivative)—to produce cell cycle arrest and apoptosis. Ado-trastuzumab emtansine is marketed under the brand name Kadcyla and is indicated for use in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. The FDA label has two precautions. First that ado-trastuzumab emtansine and trastuzumab cannot be interchanged. Second that there is a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.

生产厂家
    封装厂家
    参考
    Synthesis Reference Not Available
    General Reference
    1. FDA label.
    2. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776. Pubmed
    剂型
    规格
    化合物类型
    Type small molecule
    Classes Not Available
    Substructures Not Available
    适应症
    药理
    Indication Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment.
    Pharmacodynamics Ado-trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of ado-trastuzumab emtansine are cell cycle arrest and cell death by apoptosis.
    Mechanism of action Ado-trastuzumab emtansine is a HER2 antibody drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Ado-trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade ado-trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by ado-trastuzumab emtansine.
    Absorption The absorption/ bioavailability should be close to 100% since ado-trastuzumab emtansine is administered IV.
    Volume of distribution

    The volume of distribution of ado-trastuzumab emtansine is about 3.13 L.
    Protein binding DM1 has a plasma protein binding value of 93%.
    Metabolism
    Ado-trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes.
    Route of elimination The route of elimination has not yet been fully elucidated.
    Half life Ado-trastuzumab emtansine has a long half life of about 4 days.
    Clearance

    After IV infusion, ado-trastuzumab emtansine has a clearance of 0.68 L/day.
    Toxicity The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.
    Affected organisms
    • Humans and other mammals
    Pathways Not Available
    理化性质
    Properties
    State solid
    Experimental Properties Not Available
    Predicted Properties Not Available
    药物相互作用
    Drug Interaction
    Belimumab Avoid combination due to the increased risk of belimumab associated side effects.
    Clozapine Avoid combination due to the increased potential for agranulocytosis.
    Natalizumab Avoid combination due to the increased risk of infection.
    Phenytoin Avoid combination with phenytoin and other strong CYP3A4 inducers due to the likely increase in metabolism of ado-trastuzumab emtansine to its active component, DM1.
    Pimecrolimus Avoid combination due to the increase in immunosuppressant side effects.
    Tacrolimus Avoid combination due to the increase in immunosuppressant side effects.
    Tofacitinib Avoid combination with tofacitinib and other potent immunosuppressants due to the likely enhancement of immunosuppression.
    食物相互作用
    Not Available

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