Sánchez-Hernández José Germán, Pérez-Blanco Jonás Samuel, Rebollo Noemí, Muñoz Fernando, Prieto Vanessa, Calvo María Victoria
Pharmacy Service, University Hospital of Salamanca, Salamanca, Spain; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
Eur J Pharm Sci. 2020 Jul 1;150:105369. doi: 10.1016/j.ejps.2020.105369. Epub 2020 May 19.
Inflammatory bowel disease (IBD) is commonly treated with adalimumab. The main objective of the study was to develop a population pharmacokinetic model of adalimumab in IBD patients evaluating the potential biomarkers of disease activity and other factors and its implications in adalimumab dosing. A prospective observational study was performed in adult patients diagnosed with Crohn's disease and ulcerative colitis treated with adalimumab and following a proactive therapeutic drug monitoring of serum concentrations. Adalimumab serum concentrations (ASC) were quantified mainly prior the administration using an enzyme-linked immunosorbent assay (ELISA). A population pharmacokinetic model was developed based on 303 ASC data of 104 IBD patients using non-linear mixed effect modelling approach. Sixty-five ASC from 20 additional patients were randomly selected as an external validation group. A one-compartment model with first order absorption and elimination best describe the ASC time course. Body mass index (BMI), faecal calprotectin (FCP), unexplained decline in ASC and the specific administration pen device exhibited significant influence on apparent clearance (p-value < 0.001). FCP was the inflammatory activity biomarker showing the most relevant impact on adalimumab exposure, higher than C-reactive protein and albumin, and may be useful for adalimumab dosing adjustment. The population-based pharmacokinetic model developed adequately characterized adalimumab exposure in IBD patients. The unexplained decline in ASC, FCP, BMI and the specific administration pen device were identified as meaningful variables significantly influencing adalimumab pharmacokinetics.
炎症性肠病（IBD）通常用阿达木单抗治疗。该研究的主要目的是建立IBD患者中阿达木单抗的群体药代动力学模型，评估疾病活动的潜在生物标志物和其他因素及其对阿达木单抗给药的影响。对诊断为克罗恩病和溃疡性结肠炎的成年患者进行了一项前瞻性观察研究，这些患者接受阿达木单抗治疗并对血清浓度进行积极的治疗药物监测。阿达木单抗血清浓度（ASC）主要在给药前使用酶联免疫吸附测定（ELISA）进行定量。使用非线性混合效应建模方法，基于104例IBD患者的303个ASC数据建立了群体药代动力学模型。从另外20例患者中随机选择65个ASC作为外部验证组。具有一级吸收和消除的单室模型最能描述ASC的时间过程。体重指数（BMI）、粪便钙卫蛋白（FCP）、ASC的不明原因下降以及特定的给药笔装置对表观清除率有显著影响（p值<0.001）。FCP是对阿达木单抗暴露影响最显著的炎症活动生物标志物，其影响大于C反应蛋白和白蛋白，可能有助于调整阿达木单抗的给药剂量。所建立的基于群体的药代动力学模型充分表征了IBD患者中阿达木单抗的暴露情况。ASC的不明原因下降、FCP、BMI和特定的给药笔装置被确定为显著影响阿达木单抗药代动力学的有意义变量。
