Gastroenterology, Guy's & St Thomas' Hospital, London, UK.
Viapath Laboratories, Guy's & St Thomas' Hospital, London, UK.
Aliment Pharmacol Ther. 2020 Jul;52(2):292-302. doi: 10.1111/apt.15808. Epub 2020 Jun 7.
Significant associations between serum golimumab concentrations and favourable outcomes have been observed during both induction and maintenance therapy in ulcerative colitis (UC). However, data regarding optimal therapeutic serum golimumab concentration thresholds are limited.
To identify optimal serum golimumab concentration thresholds during induction and maintenance treatment with golimumab.
GO-LEVEL was an open label, phase IV study that included a prospective cohort of UC patients commencing golimumab, as well as a cross-sectional cohort receiving maintenance treatment. Patients commencing induction for active UC (defined as a simple clinical colitis activity index [SCCAI] >5 in addition to a raised faecal calprotectin [FC] >59μg/g or, raised C-reactive protein [CRP] [>5mg/L] or, Mayo endoscopic disease activity 2 or 3) were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare or during remission. Combined clinical-biochemical remission was defined as SCCAI ≤2 and FC <250μg/g. Serum golimumab concentrations were measured using a commercially available ELISA (LISATRACKER, Theradiag).
Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined clinical-biochemical remission at week 6. The median serum golimumab concentration of those in combined clinical-biochemical remission was significantly higher than those who were not (5.0 vs 3.1 μg/mL, respectively, P = 0.03). Receiver operating characteristic (ROC) curve analysis demonstrated 3.8 μg/mL as the optimal threshold (sensitivity 0.71, specificity 0.65, area under curve [AUC] 0.72, positive predictive value [PPV] 0.59 and negative predictive value [NPV] 0.79). Sixty-three patients were included in the maintenance cohort; 31 (49%) were in combined remission, 32 (51%) were not. The median serum golimumab concentration of those in combined remission was significantly higher (2.9 vs 2.1 μg/mL, respectively, P = 0.01). ROC curve analysis demonstrated 2.4 μg/mL as the optimal threshold (sensitivity 0.68, specificity 0.66, AUC 0.68, PPV 0.65 and NPV 0.66).
GO-LEVEL (NCT03124121) offers further evidence regarding golimumab's exposure-response relationship. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested therapeutic thresholds of 3.8 μg/mL at week 6 and 2.4 μg/mL during maintenance.
在溃疡性结肠炎（UC）的诱导和维持治疗中，均观察到血清戈利木单抗浓度与良好结局之间存在显著关联。然而，关于最佳治疗性血清戈利木单抗浓度阈值的数据有限。
确定诱导和维持治疗中戈利木单抗的最佳血清戈利木单抗浓度阈值。
GO-LEVEL 是一项开放标签、四期研究，纳入了开始接受戈利木单抗治疗的 UC 患者的前瞻性队列，以及接受维持治疗的横断面队列。开始诱导治疗的活动期 UC 患者（定义为 SCCAI＞5，同时粪便钙卫蛋白[FC]＞59μg/g，或 CRP 升高[＞5mg/L]，或 Mayo 内镜疾病活动度 2 或 3）在第 6、10 和 14 周进行评估。接受维持治疗的患者在疾病发作时或缓解期招募。联合临床生化缓解定义为 SCCAI≤2 和 FC＜250μg/g。使用市售 ELISA（LISATRACKER，Theradiag）测量血清戈利木单抗浓度。
39 例患者纳入诱导队列，其中 15 例（38%）在第 6 周达到联合临床生化缓解。联合临床生化缓解患者的中位血清戈利木单抗浓度明显高于未缓解患者（分别为 5.0μg/ml 和 3.1μg/ml，P=0.03）。受试者工作特征（ROC）曲线分析显示 3.8μg/ml 为最佳阈值（灵敏度 0.71，特异性 0.65，曲线下面积[AUC]0.72，阳性预测值[PPV]0.59，阴性预测值[NPV]0.79）。63 例患者纳入维持队列；31 例（49%）处于联合缓解状态，32 例（51%）未缓解。联合缓解患者的中位血清戈利木单抗浓度明显较高（分别为 2.9μg/ml 和 2.1μg/ml，P=0.01）。ROC 曲线分析显示 2.4μg/ml 为最佳阈值（灵敏度 0.68，特异性 0.66，AUC 0.68，PPV 0.65，NPV 0.66）。
GO-LEVEL（NCT03124121）进一步提供了关于戈利木单抗暴露-反应关系的证据。临床医生可能会考虑使用治疗药物监测来优化戈利木单抗的剂量，以达到我们建议的 6 周时 3.8μg/ml 和维持时 2.4μg/ml 的治疗阈值。
