Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, JB Winsløwsvej 19, 2, DK-5000, Odense C, Denmark.
Department of Rheumatology, Odense University Hospital, Odense, Denmark.
Eur J Clin Pharmacol. 2023 Dec;79(12):1687-1698. doi: 10.1007/s00228-023-03578-1. Epub 2023 Oct 13.
Inflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis.
In a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13, 2021). In a retrospective study, the 4β-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor.
In the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and C indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64-0.99 and C GMR: 0.58, 95% CI: 0.37-0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72-1.46 and C GMR 1.03, 95% CI 0.72-1.47). No effect on the 4β-hydroxycholesterol/cholesterol ratio was observed in the retrospective study.
Based on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect. Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.
炎症会抑制细胞色素 P450（CYP）酶的活性，而单次剂量的白细胞介素 6 受体拮抗剂（抗-IL-6R）可逆转这种作用。在这里，我们评估了连续抗-IL-6R 治疗对类风湿关节炎患者的影响。
在一项临床药代动力学试验中，在接受抗-IL-6R 治疗 3 周和 12 周前后，给予巴塞尔鸡尾酒以评估 CYP 酶活性（于 2021 年 4 月 13 日在 ClinicalTrials.gov 数据库（标识符 NCT04842981）注册）。在回顾性研究中，在接受抗-IL-6R 治疗 3 个月和 6 个月前后，以 4β-羟胆固醇/胆固醇比值作为 CYP3A4 活性的生物标志物进行测量。对照组为开始使用肿瘤坏死因子-α（TNF-α）抑制剂的患者。
在临床药代动力学试验（n=3）中，由于样本量有限，咪达唑仑代谢比（CYP3A4）的结果不确定。与基线相比，抗-IL-6R 治疗 3 周后，咪达唑仑 AUC 和 C 表明对 CYP3A4 活性的影响较弱（AUC 几何均数比（GMR）：0.80，95%CI：0.64-0.99 和 C GMR：0.58，95%CI：0.37-0.91），治疗 12 周后恢复到基线水平（AUC GMR 1.02，95%CI：0.72-1.46 和 C GMR 1.03，95%CI 0.72-1.47）。在回顾性研究中，未观察到 4β-羟胆固醇/胆固醇比值的变化。
基于三名患者的稀疏数据，连续抗-IL-6R 治疗似乎会导致类风湿关节炎患者 CYP3A4 活性的急性但短暂增加，这可能是由于炎症抑制的 CYP 活性的正常化。需要进一步的研究来了解这种假定的短暂效应背后的机制。
于 2021 年 4 月 13 日在 ClinicalTrials.gov 数据库（标识符 NCT04842981）注册。
