Schräpel Christina, Kovar Lukas, Selzer Dominik, Hofmann Ute, Tran Florian, Reinisch Walter, Schwab Matthias, Lehr Thorsten
Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany.
Pharmaceutics. 2021 Aug 31;13(9):1368. doi: 10.3390/pharmaceutics13091368.
Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing regimens and improve therapy. The aim of this study was to evaluate the predictive performance of published infliximab population pharmacokinetic models for IBD patients with an external data set. The data set consisted of 105 IBD patients with 336 infliximab concentrations. Literature review identified 12 published models eligible for external evaluation. Model performance was evaluated with goodness-of-fit plots, prediction- and variability-corrected visual predictive checks (pvcVPCs) and quantitative measures. For anti-drug antibody (ADA)-negative patients, model accuracy decreased for predictions > 6 months, while bias did not increase. In general, predictions for patients developing ADA were less accurate for all models investigated. Two models with the highest classification accuracy identified necessary dose escalations (for trough concentrations < 5 µg/mL) in 88% of cases. In summary, population pharmacokinetic modeling can be used to individualize infliximab dosing and thereby help to prevent infliximab trough concentrations dropping below the target trough concentration. However, predictions of infliximab concentrations for patients developing ADA remain challenging.
英夫利昔单抗被批准用于治疗包括炎症性肠病（IBD）在内的多种慢性炎症性疾病。然而，英夫利昔单抗谷浓度的高度变异性与不同的反应率相关。使用群体药代动力学模型的模型指导精准给药（MIPD）有助于个体化英夫利昔单抗给药方案并改善治疗效果。本研究的目的是使用一个外部数据集评估已发表的针对IBD患者的英夫利昔单抗群体药代动力学模型的预测性能。该数据集由105例IBD患者的336个英夫利昔单抗浓度组成。文献综述确定了12个符合外部评估条件的已发表模型。通过拟合优度图、预测和变异性校正的视觉预测检查（pvcVPC）以及定量指标来评估模型性能。对于抗药物抗体（ADA）阴性的患者，预测超过6个月时模型准确性下降，而偏差并未增加。总体而言，对于所有研究的模型，对出现ADA的患者的预测准确性较低。两个分类准确性最高的模型在88%的病例中识别出了必要的剂量增加（针对谷浓度<5μg/mL）。总之，群体药代动力学建模可用于个体化英夫利昔单抗给药，从而有助于防止英夫利昔单抗谷浓度降至目标谷浓度以下。然而，对于出现ADA的患者的英夫利昔单抗浓度预测仍然具有挑战性。
