Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Pediatrics, Zaans Medical Center, Zaandam, The Netherlands.
Paediatr Drugs. 2024 Jul;26(4):441-450. doi: 10.1007/s40272-024-00629-7. Epub 2024 Apr 17.
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability.
Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates.
A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure.
Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.
幼年特发性关节炎（JIA）是一种主要影响儿童关节的慢性自身免疫性疾病。值得注意的是，它常与葡萄膜炎同时发生。阿达木单抗是一种单克隆抗 TNF 抗体，对两种疾病均有效。深入了解 JIA 中阿达木单抗的药代动力学（PK）对于推进更个性化的治疗方法至关重要。本研究的目的是评估 JIA 中阿达木单抗的群体 PK 特征，并解释其变异性的原因。
阿达木单抗和抗药物抗体浓度从前 JIA 患者的图表中回顾性检索。最初，评估了五个基于文献的阿达木单抗群体 PK 模型，以评估它们描述 JIA 队列中观察到的浓度-时间曲线的能力。这些模型包括一个专门针对儿科克罗恩病人群的模型，以及四个源自健康受试者和类风湿关节炎患者的成人人群研究的模型。随后，使用 NONMEM 软件开发了一个针对 JIA 人群的新型群体 PK 模型。然后使用最终的 PK 模型进行 Monte Carlo 模拟，以可视化 JIA 患者中阿达木单抗的浓度-时间曲线及其对协变量的影响。
评估了 50 名 JIA 患者的队列，其中有 78 个阿达木单抗样本。平均年龄为 11.8±3.9 岁，中位数体重为 49kg（四分位距 29.4-59.8kg）。所有文献模型均能充分描述 JIA 中的浓度-时间曲线。在治疗维持阶段的类风湿关节炎患者中开发的最佳模型，为估计 JIA 中的清除率提供了依据，结果为 70kg 患者每天 0.37L。患者体重、抗药物抗体、甲氨蝶呤的使用、CRP 水平和葡萄膜炎的合并症被发现对阿达木单抗的清除率有显著影响，这使患者间的变异性从 58.6%降低到 28.0%。在模拟患者人群的稳态下，平均谷浓度为 7.4±5.5mg/L。根据患者体重，每两周 20mg 和 40mg 的两种给药方案导致模拟的总体药物暴露相当。
五个文献模型有效地描述了本儿科队列中阿达木单抗的 PK，突出了将现有模型外推到儿科人群的潜力。新的 JIA 模型证实了几个已知协变量的影响，并发现药物清除率与甲氨蝶呤使用（降低）和葡萄膜炎（升高）之间存在新的关联，这可能对 JIA 的个体化给药具有临床意义。
