Steenholdt Casper, Lorentsen Ruben Due, Henneberg Jon, Petersen Pernille Nørgaard, Brynskov Jørn
Department of Medical Gastroenterology, Odense University Hospital, Winsløws Vej 4, 5000, Odense, Denmark.
Research Unit of Medical Gastroenterology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
BioDrugs. 2025 Jun 18. doi: 10.1007/s40259-025-00730-4.
Increasing therapeutic options for inflammatory bowel disease calls for tools to aid choice of sequencing. We investigated if pharmacokinetic (PK) and pharmacodynamic (PD) failure mechanisms prompting therapy change influenced subsequent outcomes when switching to a different biologic drug class.
Retrospective single-center cohort study including patients treated first with tumor necrosis factor (TNF) inhibitors, followed by vedolizumab, and then ustekinumab. Clinical and objective disease remission were conventionally classified by validated indices. PK-PD failure was defined according to maintenance drug concentrations (PK below thresholds and PD above thresholds): infliximab 8.0 µg/mL, adalimumab 12.0 µg/mL, golimumab 1.4 µg/mL, vedolizumab 15 µg/mL. Primary treatment failure despite dose intensification was ascribed to PD. Primary endpoints were steroid-free treatment persistence and 1-year remission.
The study included 112 patients switching from TNF inhibitors to vedolizumab (infliximab n = 61, adalimumab n = 32, golimumab n = 16, certolizumab pegol n = 3) and 31 subsequently to ustekinumab. Treatment persistence on vedolizumab did not differ between patients discontinuing TNF inhibitors due to PK (n = 28, 31%) or PD (n = 63, 69%) (mean 989 days [95% confidence interval: 554-1424] vs. 951 [659-1242], p = 0.93). One-year steroid-free clinical and objective remission rates on VDZ were also comparable between PK-PD groups (29% vs. 35%, p = 0.63 and 35% vs. 43%, p = 0.48, respectively). Findings for UST were similar. Sensitivity analyses with exclusion of primary non-responders and multivariate analyses correcting for potential confounders supported findings.
PK-PD failure mechanisms do not appear to influence subsequent treatment outcomes when switching to biologics with different modes of action. Sequencing may rather rely on aspects such as efficacy, safety, and costs.
炎症性肠病治疗选择的增加需要有助于选择治疗顺序的工具。我们研究了促使治疗改变的药代动力学（PK）和药效学（PD）失败机制在换用不同生物制剂药物类别时是否会影响后续结局。
回顾性单中心队列研究，纳入先接受肿瘤坏死因子（TNF）抑制剂治疗，随后接受维多珠单抗治疗，然后接受乌司奴单抗治疗的患者。临床和客观疾病缓解情况通过经过验证的指标进行常规分类。PK-PD失败根据维持药物浓度定义（PK低于阈值且PD高于阈值）：英夫利昔单抗8.0μg/mL、阿达木单抗12.0μg/mL、戈利木单抗1.4μg/mL、维多珠单抗15μg/mL。尽管增加剂量但仍出现的主要治疗失败归因于PD。主要终点为无类固醇治疗持续时间和1年缓解率。
该研究纳入了112例从TNF抑制剂换用维多珠单抗的患者（英夫利昔单抗n = 61、阿达木单抗n = 32、戈利木单抗n = 16、聚乙二醇化赛妥珠单抗n = 3），以及31例随后换用乌司奴单抗的患者。因PK（n = 28，31%）或PD（n = 63，69%）而停用TNF抑制剂的患者在维多珠单抗上的治疗持续时间无差异（平均989天[95%置信区间：554 - 1424]对951天[659 - 1242]，p = 0.93）。PK-PD组之间在VDZ上的1年无类固醇临床和客观缓解率也相当（分别为29%对35%，p = 0.63以及35%对4…
