Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy.
Dipartimento di Oncologia e Emato-Oncologia, Italy.
Pharmacol Res. 2016 Sep;111:592-599. doi: 10.1016/j.phrs.2016.07.015. Epub 2016 Jul 18.
The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction.
治疗性单克隆抗体（mAbs）的清除通常不涉及细胞色素 P450（CYP450）介导的代谢或与细胞膜转运体的相互作用，因此 mAbs 和小分子药物的药代动力学相互作用有限。然而，药物可能通过调节免疫反应来影响 mAbs 的清除（例如，甲氨蝶呤降低英夫利昔单抗、阿达木单抗和戈利木单抗的清除率，可能是由于甲氨蝶呤抑制了针对 mAbs 的抗体的形成）。此外，作为细胞因子调节剂的 mAbs 可能通过对 P450 酶表达的影响来改变药物的代谢。例如，细胞因子调节剂，如托珠单抗（抗 IL-6 受体抗体），可能会逆转 IL-6 对 CYP 底物的“抑制”作用，从而使 CYP 活性“正常化”。最后，药物可能通过增加或减少细胞表面 mAbs 靶点的表达水平来改变 mAbs 的清除率。例如，他汀类药物和贝特类药物诱导 PCSK9 表达，从而增加了对阿利鲁单抗和依洛尤单抗（抗 PCSK9 抗体）的细胞摄取和清除。在本综述中，我们将概述 mAbs 的药代动力学特性，并与 mAbs-小分子药物相互作用的最相关实例相关联。
