Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg⁻¹) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration–time profiles of infliximab. Typical clearance of infliximab was 0.404 L day⁻¹ and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (B_max was 19.8 pg mL⁻¹ and the dissociation constant (K_ss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.

中文翻译：

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溃疡性结肠炎患者中肿瘤坏死因子介导的英夫利昔单抗治疗。

溃疡性结肠炎（UC）是一种炎症性肠病，通常会影响结肠。患有活动性UC的患者血清和结肠组织中的肿瘤坏死因子（TNF）浓度升高。英夫利昔单抗是针对TNF的单克隆抗体，具有高亲和力。报告了单克隆抗体的靶标介导的药物处置（TMDD），这意味着其药代动力学受靶标高亲和力影响。在这里，提出了一种TMDD模型来描述英夫利昔单抗和UC患者TNF之间的相互作用。使用了20例中度至重度UC患者的数据。患者接受标准英夫利昔单抗诱导治疗（5 mg kg ^-1）在第0周，然后在第2周和第6周输注。在第0天（输注后1小时），1、4、7、11、14、18、21，参见图28和42。使用非线性混合效应模型（NONMEM）评估了绑定模型，TMDD模型和准稳态（QSS）近似值。两室模型最能描述英夫利昔单抗的浓度-时间曲线。英夫利昔单抗的典型清除率为0.404 L第^-1天，并随着抗药物抗体的存在和白蛋白浓度的降低而增加。TMDD-QSS模型最好地描述了药代动力学和药效学数据。TNF基线（B _max为19.8 pg mL ^-1和离解常数（K _ss）为13.6 nM。该模型最终可用于研究TNF抑制与对IFX治疗反应之间的关系。