Primas Christian, Reinisch Walter, Panetta John C, Eser Alexander, Mould Diane R, Dervieux Thierry
Division of Gastroenterology & Hepatology, Medical University of Vienna, A-1090 Vienna, Austria.
St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
J Clin Med. 2022 Jun 9;11(12):3316. doi: 10.3390/jcm11123316.
Background: Substantial inter-and intra-individual variability of Infliximab (IFX) pharmacokinetics necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Methods: Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings’s regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. Results: In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/mL from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming’s slope = 0.90 and R2 = 0.87. Observed end cycle and forecasted trough levels above 5 µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7−30.2; OR = 21.0 CI95%: 3.4−127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/mL from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). Conclusions: These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.
英夫利昔单抗（IFX）的药代动力学在个体间和个体内存在显著差异，因此需要采用个性化给药方法。在此，我们评估了一个模型指导的精准给药（MIPD）工具在预测炎症性肠病（IBD）患者英夫利昔单抗（IFX）谷浓度水平与疾病状态及循环肿瘤坏死因子-α（TNF-α）之间的关系时的性能。
纳入接受每8周一次英夫利昔单抗维持治疗且签署知情同意书的患者。收集周期中期样本，测定英夫利昔单抗、抗英夫利昔单抗抗体、白蛋白，并使用非线性混合效应模型结合贝叶斯数据同化进行加权分析，以预测谷浓度水平。使用德明回归评估预测的谷浓度水平与观察到的英夫利昔单抗谷浓度水平相比的准确性。使用逻辑回归和线性混合效应模型分析英夫利昔单抗水平、基于C反应蛋白（CRP）的临床缓解与TNF-α水平之间的关联。
在41例接受英夫利昔单抗治疗的患者中（中位剂量 = 5.3 mg/Kg），从周期中期到周期结束时间点，英夫利昔单抗的中位水平分别从13.0降至3.9 μg/mL。周期中期英夫利昔单抗水平预测谷浓度时德明斜率 = 0.90，R2 = 0.87。观察到的周期结束时水平和预测的谷浓度水平高于5 μg/mL与基于CRP的临床缓解相关（OR分别为7.2，95%CI：1.7−30.2；OR为21.0，95%CI：3.4−127.9）（p < 0.01）。从周期中期到周期结束时间点，TNF-α的中位水平分别从4.6升至8.0 pg/mL（p < 0.01）。CRP和TNF-α水平与英夫利昔单抗水平降低独立且相加相关（p < 0.01）。
这些数据证实了我们的MIPD工具在预测IBD患者英夫利昔单抗谷浓度水平方面的价值。血清TNF-α和CRP反映了影响药物暴露的炎症负担。
