Klotz Ulrich, Teml Alexander, Schwab Matthias
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Clin Pharmacokinet. 2007;46(8):645-60. doi: 10.2165/00003088-200746080-00002.
Tumor necrosis factor-alpha (TNFalpha) is a key proinflammatory cytokine involved in chronic inflammatory diseases. Infliximab, a chimeric (human-murine) monoclonal IgG1 anti-TNFalpha antibody, is used in the treatment of Crohn's disease (including fistulising disease) and rheumatoid arthritis (in combination with methotrexate) if standard treatments have failed. The indications for infliximab have recently been expanded to include ankylosing spondylitis, psoriatic arthritis, psoriasis and ulcerative colitis. The biological agent infliximab is given by multiple intravenous infusions in a dosage of 3-5 mg/kg (initially at weeks 0, 2 and 6; subsequently in intervals of 4-8 weeks). In controlled trials, clinical response rates of 20-40% have been achieved with such regimens in Crohn's disease and rheumatoid arthritis. However, the therapeutic benefits must be balanced against the risks of a variety of severe adverse events (e.g. severe infections including tuberculosis, hepatotoxicity, infusion reactions, serum sickness-like disease and lymphoma). Following single and multiple infusions of infliximab, no relevant differences in median concentration-time profiles have been observed between patients with Crohn's disease, patients with rheumatoid arthritis and patients with psoriasis. The apparent volume of distribution of the high-molecular-weight infliximab (149.1 kDa) is low (3-6L) and represents the intravascular space. The long persistence in this compartment (elimination half-life 7-12 days, mean residence time 12-17 days) is due to the very low systemic clearance of about 11-15 mL/hour (0.18-0.25 mL/minute). Elimination of infliximab is most probably accomplished through degradation by unspecific proteases. During multiple infusions (every 4-8 weeks), no accumulation was observed, and serum concentrations and the area under the plasma concentration-time curve of infliximab increased in proportion to the infused dose, indicating linear pharmacokinetics. Co-medication with methotrexate delayed the decline in the serum concentrations of infliximab. When relating serum concentrations to the clinical response in patients with rheumatoid arthritis and patients with Crohn's disease, it can be assumed that trough concentrations above 1 microg/mL could be used as a kind of therapeutic target. In the future, identification of biomarkers for (non-)response and risk factors for adverse drug reactions would be very helpful. Furthermore, combined biological, pharmacokinetic, pharmacogenomic and clinical studies have not yet been performed and are needed to optimise the therapeutic potential of infliximab, which is currently established as a rescue treatment in refractory patients.
肿瘤坏死因子-α（TNFα）是一种参与慢性炎症性疾病的关键促炎细胞因子。英夫利昔单抗是一种嵌合（人-鼠）单克隆IgG1抗TNFα抗体，用于治疗克罗恩病（包括瘘管病）和类风湿关节炎（与甲氨蝶呤联合使用），前提是标准治疗失败。英夫利昔单抗的适应证最近已扩大到包括强直性脊柱炎、银屑病关节炎、银屑病和溃疡性结肠炎。生物制剂英夫利昔单抗通过多次静脉输注给药，剂量为3 - 5mg/kg（最初在第0、2和6周；随后每隔4 - 8周一次）。在对照试验中，这种方案在克罗恩病和类风湿关节炎中取得了20% - 40%的临床缓解率。然而，必须在治疗益处与各种严重不良事件（如包括结核病在内的严重感染、肝毒性、输液反应、血清病样疾病和淋巴瘤）的风险之间进行权衡。在单次和多次输注英夫利昔单抗后，克罗恩病患者、类风湿关节炎患者和银屑病患者之间在中位浓度-时间曲线方面未观察到相关差异。高分子量英夫利昔单抗（149.1kDa）的表观分布容积较低（3 - 6L），代表血管内空间。在该腔室中的长滞留时间（消除半衰期7 - 12天，平均驻留时间12 - 17天）是由于极低的全身清除率，约为11 - 15mL/小时（0.18 - 0.25mL/分钟）。英夫利昔单抗的消除很可能是通过非特异性蛋白酶降解来完成的。在多次输注（每4 - 8周一次）期间，未观察到蓄积现象，英夫利昔单抗的血清浓度和血浆浓度-时间曲线下面积与输注剂量成比例增加，表明具有线性药代动力学。与甲氨蝶呤联合用药可延缓英夫利昔单抗血清浓度的下降。当将血清浓度与类风湿关节炎患者和克罗恩病患者的临床反应相关联时，可以假设谷浓度高于1μg/mL可作为一种治疗靶点。未来，识别（无）反应的生物标志物和药物不良反应的风险因素将非常有帮助。此外，尚未进行联合生物学、药代动力学、药物基因组学和临床研究，而这些研究对于优化英夫利昔单抗的治疗潜力是必要的，目前英夫利昔单抗被确立为难治性患者的挽救治疗药物。
