Hospital Pharmacy, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.
Gastroenterology & Hepatology Department, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.
J Pharmacokinet Pharmacodyn. 2019 Dec;46(6):543-551. doi: 10.1007/s10928-019-09652-5. Epub 2019 Sep 5.
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) 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 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 was 19.8 pg mL and the dissociation constant (K) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.
溃疡性结肠炎（UC）是一种炎症性肠病，通常影响结肠。活动期 UC 患者血清和结肠组织中肿瘤坏死因子（TNF）浓度升高。英夫利昔单抗是一种针对 TNF 的单克隆抗体，与 TNF 具有高亲和力。靶向介导的药物处置（TMDD）已报道用于单克隆抗体，这意味着它们的药代动力学受到高靶亲和力的影响。在这里，提出了一个 TMDD 模型来描述 UC 患者中英夫利昔单抗与 TNF 之间的相互作用。使用了 20 名中重度 UC 患者的数据。患者在第 0 周接受标准英夫利昔单抗诱导治疗（5mg/kg），然后在第 2 周和第 6 周进行输注。在第 0 天（输注后 1 小时）、第 1 天、第 4 天、第 7 天、第 11 天、第 14 天、第 18 天、第 21 天、第 28 天和第 42 天测量 IFX、抗药物抗体和 TNF 血清浓度。使用非线性混合效应建模（NONMEM）评估结合模型、TMDD 模型和准稳态（QSS）逼近。两室模型最好地描述了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/day，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）的估计值为 19.8pg/mL，解离常数（K）为 13.6nM。该模型最终可用于研究 TNF 抑制与 IFX 治疗反应之间的关系。
