甲氨蝶呤影响抗肿瘤坏死因子类单抗药物消除的作用机制及定量关系研究

Anti-tumor necrosis factor-α monoclonal antibody (anti-TNF-α mAb) is being commonly used for the treatment of rheumatic diseases in combination with the methotrexate. The coadministration of methotrexate has been found to significantly decrease the clearance of anti-TNF-α mAb. However, this result conflicts with the classical viewpoint that small molecule drugs seldom affect the elimination of monoclonal antibodies. Neonatal Fc receptor (FcRn) can reduces the elimination rate of antibodies by protecting them from elimination in cell. Furthermore, we found that methotrexate increased the expression of FcRn in rat tissues. FcRn may play a key role in the effect of methotrexate on the clearance of anti-TNF-α mAb. In this study, we investigated the mechanism of methorexate affecting the elimination of anti-TNF-α mAb, and proposed a hypothesis that FcRn was mediated by methorexate to affect the clearance of anti-TNF-α mAb. In addition, we constructed a new population pharmacokinetic model of anti-TNF-α mAb in order to quantitatively study the effects of methotrexate and FcRn affinity on the clearance of anti-TNF-α mAb. The proposed hypothesis will provide a new idea for the study of the interaction between small molecule drugs and monoclonal antibodies.

抗肿瘤坏死因子（TNF-α）类单抗药物与甲氨蝶呤联合用药已成为风湿免疫疾病的常用药物治疗方案。抗TNF-α单抗药物与甲氨蝶呤合用时，甲氨蝶呤可以显著影响抗TNF-α单抗药物的清除率。而现有“化学小分子药物不会显著影响单克隆抗体药物消除”的观点无法解释该现象。新生儿抗体可结晶片段受体（FcRn）可以保护抗体在细胞内免遭降解消除，并且我们前期研究发现，甲氨蝶呤可以增加大鼠组织中FcRn表达量。我们推测FcRn可能在甲氨蝶呤影响抗TNF-α单抗药物清除率中发挥重要作用。因此本研究提出“FcRn介导甲氨蝶呤影响抗TNF-α单抗药物清除率”的假说，研究甲氨蝶呤影响抗TNF-α单抗药物清除率的作用机制；并建立抗TNF-α单抗药物的群体药动学模型，阐明甲氨蝶呤联用和FcRn亲和力影响抗TNF-α单抗药物消除率的定量关系。本研究提出的新假说，将会为化学小分子药物与单克隆抗体药物的相互作用研究指引新方向。

抗肿瘤坏死因子（TNF-α）类单抗药物与甲氨蝶呤联合用药已成为风湿免疫疾病的常用药物治疗方案。抗TNF-α单抗药物与甲氨蝶呤合用时，甲氨蝶呤可以显著影响抗TNF-α单抗药物的清除率。为了阐明甲氨蝶呤影响抗TNF-α单抗药物清除率的具体机制及定量关系，本研究首先在大鼠和HepG2细胞中分别进行实验，探究甲氨蝶呤对新生儿抗体可结晶片段受体（FcRn）含量的影响。研究结果表明甲氨蝶呤可以增加肝、肾、肠等组织中的FcRn含量，提高FcRn对单克隆抗体药物的保护作用。随后，我们分别在大鼠和强直性脊柱炎患者中进行甲氨蝶呤和阿达木单抗的药物相互作用研究，以确证FcRn在甲氨蝶呤影响阿达木单抗清除率中的作用。研究结果表明，甲氨蝶呤联用可以使大鼠和患者体内FcRn含量显著增加，同时也会使阿达木单抗清除率显著降低，而当甲氨蝶呤对FcRn含量的影响被抗FcRn抗体抑制时，阿达木单抗清除率则无明显变化。该实验结果确证FcRn在甲氨蝶呤降低阿达木单抗清除率中发挥了重要作用。最后，我们基于单抗药物新型药动学模型以及强直性脊柱炎患者中阿达木单抗的药动学数据，构建了强直性脊柱炎患者中的阿达木单抗群体药动学模型，获得了阿达木单抗在强直性脊柱炎患者中的群体药动学参数。本研究的研究方法及所获得的研究成果，有助于推动临床实践中抗TNF-α单抗药物的合理用药。