Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.
Monash University, Eastern Health Clinical School, Melbourne, VIC, Australia.
BioDrugs. 2024 Sep;38(5):691-702. doi: 10.1007/s40259-024-00673-2. Epub 2024 Aug 22.
The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision.
This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis.
A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn's disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn's disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively.
The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p < 0.01). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest infliximab trough levels (all p < 0.01).
This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.
解决因治疗药物血药浓度低于治疗窗下限而导致应答丧失的最佳英夫利昔单抗剂量强化策略仍不确定，强化治疗后药物浓度和治疗目标是否会影响这一决策也不确定。
本药代动力学模拟研究旨在确定英夫利昔单抗剂量强化策略，以达到克罗恩病和溃疡性结肠炎的临床和客观治疗目标相关的强化治疗后药物浓度下限。
应用验证过的英夫利昔单抗药代动力学模型，对 200 名模拟患者进行分析，以确定在标准（5mg/kg，每 8 周 1 次）治疗 30 周后药物浓度低于治疗窗下限（<3.00mg/L）的患者，随后在接下来的 32 周内应用 10 种剂量强化策略。主要结局是评估在强化治疗 32 周后达到与内镜缓解相关的英夫利昔单抗药物浓度下限（溃疡性结肠炎>7.50mg/L，克罗恩病>9.70mg/L）的模拟患者比例，肛周瘘管愈合（克罗恩病>10.10mg/L）和临床改善（溃疡性结肠炎>3.70mg/L，克罗恩病>7.00mg/L）作为次要结局。所有结局均按剂量强化强度分层，分别定义标准（≤10mg/kg，每 8 周 1 次或 5mg/kg，每 4 周 1 次；n=5）和强化（>10mg/kg，每 8 周 1 次或 5mg/kg，每 4 周 1 次；n=5）治疗策略。
中位强化前英夫利昔单抗药物浓度下限为 0.91mg/L（四分位间距 1.37）。强化治疗策略更有可能达到与内镜缓解相关的英夫利昔单抗药物浓度下限（溃疡性结肠炎 36.48%比 10.80%，克罗恩病 25.98%比 4.68%）、肛周瘘管愈合（24.52%比 4.36%）和临床改善（溃疡性结肠炎 61.90%比 34.86%，克罗恩病 40.32%比 12.08%），而标准强化策略则较低（均 p<0.01）。当控制 32 周内累积（mg/kg）英夫利昔单抗剂量时，同时增加剂量和缩短间隔的策略可达到最高的英夫利昔单抗药物浓度下限（均 p<0.01）。
本基于模拟的分析强调了在克罗恩病和溃疡性结肠炎中使用与理想治疗目标相关的强化治疗后英夫利昔单抗药物浓度下限来指导英夫利昔单抗剂量强化策略选择的潜力。强化剂量强化策略，特别是同时增加剂量和缩短间隔的策略，似乎比标准剂量强化策略能达到更高的英夫利昔单抗药物浓度下限。这在追求严格的终点（如内镜缓解和瘘管愈合）时尤为重要，这些终点与更高的英夫利昔单抗药物浓度下限密切相关。这些发现需要在真实队列中进行验证。
