Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Basel, Switzerland.
Division of Pediatric Rheumatology, Department of Pediatrics and Autoinflammation Reference Centre Tuebingen (arcT), University Hospital Tuebingen, Tuebingen, Germany.
Pediatr Rheumatol Online J. 2024 Jan 2;22(1):5. doi: 10.1186/s12969-023-00930-8.
In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2-8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate.
A two-center prospective study in PRD patients aged 2-18 years treated with adalimumab and methotrexate (G) or adalimumab alone (G) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1-9 (maximum concentration; C), and 10-14 days (minimum concentration; C) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized C were compared between G and G using a standard t-test.
Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. G included more females (71.4%; G 35.7%, p = 0.13). At first study visit, children in G had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to G (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in G had a 27% higher median overall exposure compared to G, although median C adalimumab values were statistically not different (p = 0.3). C values ≥ 8 mg/L (upper limit RA) were more frequently observed in G versus G (79% versus 64%). Overall, a wide range of C values was observed in PRD (0.5 to 26 mg/L).
This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure.
NCT04042792 , registered 02.08.2019.
在儿科风湿性疾病（PRD）中，阿达木单抗的剂量使用固定的基于体重的区间，而不管是否使用甲氨蝶呤进行联合治疗、疾病活动度（DA）或其他可能影响阿达木单抗药代动力学（PK）的因素。在类风湿关节炎（RA）中，阿达木单抗的暴露浓度在 2-8mg/L 之间与临床反应相关。关于 PRD 中阿达木单抗的数据很少。因此，本研究旨在分析 PRD 患者在使用/不使用甲氨蝶呤治疗时阿达木单抗的 PK 及其变异性。
对 2 家中心的 28 例年龄在 2-18 岁的 PRD 患者进行了前瞻性研究，这些患者接受阿达木单抗联合甲氨蝶呤（G 组）或阿达木单抗单药治疗（G 组）≥12 周。在开始使用阿达木单抗后 1-9 天（最大浓度；C）和 10-14 天（最小浓度；C）收集阿达木单抗浓度。使用酶联免疫吸附试验（定量下限：0.5mg/L）分析浓度。使用标准 t 检验比较 G 组和 G 组之间的对数正态化 C。
28 例患者（每组 14 例）完成了研究，诊断为幼年特发性关节炎（71.4%）、非感染性葡萄膜炎（25%）或慢性复发性多灶性骨髓炎（3.6%）。G 组中女性比例较高（71.4%；G 组为 35.7%，p=0.13）。在首次研究访视时，G 组患者的阿达木单抗暴露时间略长（17.8 个月[IQR 9.6，21.6]），而 G 组为 15.8 个月[IQR 8.5，30.8]，p=0.8）。两组的阿达木单抗剂量相似（中位数剂量为 40mg 每 14 天），且观察到的疾病活动度较低。与 G 组相比，G 组患者的总体暴露中位数高 27%，尽管阿达木单抗的 C 值中位数在统计学上没有差异（p=0.3）。G 组中阿达木单抗 C 值≥8mg/L（RA 上限）的比例高于 G 组（79%比 64%）。总体而言，PRD 中阿达木单抗的暴露值范围很广（0.5-26mg/L）。
本研究揭示了 PRD 中阿达木单抗暴露的高度异质性。与阿达木单抗单药治疗相比，阿达木单抗联合甲氨蝶呤治疗时的阿达木单抗暴露量倾向更高，尽管差异无统计学意义。大多数患儿的阿达木单抗暴露量超过了具有临床反应的 RA 报道值，尤其是在联合使用甲氨蝶呤时。这突显了需要进一步研究，以在 PRD 中建立基于模型的个体化治疗策略，避免药物暴露不足或过量。
NCT04042792 ，注册于 2019 年 8 月 2 日。
