Yarur Andres J, McGovern Dermot, Abreu Maria T, Cheifetz Adam, Papamichail Konstantinos, Deepak Parakkal, Bruss Alexandra, Beniwal-Patel Poonam, Dubinsky Marla, Targan Stephan R, Melmed Gil Y
Division of Gastroenterology and Hepatology, Center for Inflammatory Bowel Diseases, Cedars-Sinai Medical Center, Los Angeles, California; Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Division of Gastroenterology and Hepatology, Center for Inflammatory Bowel Diseases, Cedars-Sinai Medical Center, Los Angeles, California.
Clin Gastroenterol Hepatol. 2023 Oct;21(11):2908-2917.e10. doi: 10.1016/j.cgh.2022.10.016. Epub 2022 Oct 22.
The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs).
A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 10 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 10 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 10 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 10 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts.
Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.
本研究旨在评估6-硫鸟嘌呤核苷酸（6-TGN）水平及口服甲氨蝶呤的使用与生物制剂药代动力学之间的关系。
这是一项前瞻性队列研究，纳入接受英夫利昔单抗、维多珠单抗或乌司奴单抗维持剂量单药治疗或与硫嘌呤或口服甲氨蝶呤联合治疗的炎症性肠病患者。我们收集了6-TGN浓度、生物标志物水平以及临床和内镜下疾病活动度。主要结局指标为英夫利昔单抗、维多珠单抗和乌司奴单抗的浓度以及抗药物抗体（ADA）。
共招募了369例患者（113例使用英夫利昔单抗，133例使用维多珠单抗，123例使用乌司奴单抗）。与单药治疗相比，6-TGN水平≥每8×10⁶个红细胞（RBC）146 pmol的患者以及接受硫嘌呤或口服甲氨蝶呤联合治疗的患者英夫利昔单抗浓度显著更高（硫嘌呤联合6-TGN≥每8×10⁶个RBC 146 pmol时英夫利昔单抗中位水平为17.4 μg/mL，甲氨蝶呤联合时为17.1 μg/mL，英夫利昔单抗单药治疗时为3.9 μg/mL；两组比较P = 0.001）。然而，免疫调节剂的使用及6-TGN浓度与维多珠单抗（硫嘌呤联合6-TGN≥每8×10⁶个RBC 152 pmol时维多珠单抗中位水平为8.8 μg/mL，甲氨蝶呤联合时为6.8 μg/mL，维多珠单抗单药治疗时为10.5 μg/mL；两组比较P>0.05）或乌司奴单抗中位浓度（硫嘌呤联合6-TGN≥每8×10⁶个RBC 154 pmol时乌司奴单抗中位水平为5.0 μg/mL，甲氨蝶呤联合时为5.2 μg/mL，乌司奴单抗单药治疗时为7.0 μg/mL；两组比较P>0.05）均无关联。14例（12%）患者有抗英夫利昔单抗抗体，而其他药物队列中各有1例患者有ADA。
达到更高的6-TGN水平或使用甲氨蝶呤可改善英夫利昔单抗的药代动力学。相反，这些数据不支持联合使用维多珠单抗或乌司奴单抗来增强药代动力学。
