Background

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing.

Objective

The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance.

Methods

This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d’Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM).

Results

Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, V_c, and V_p (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, V_c, and V_p were 19.33, 16.42, and 36.02%, respectively.

Conclusions

A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

中文翻译：

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多态性和其他生物标志物对小儿炎症性肠病英夫利昔单抗暴露的影响：群体药代动力学模型的开发

背景

英夫利昔单抗的治疗药物监测（TDM）已被证明是治疗炎症性肠病（IBD）的有效策略。群体药代动力学 (PopPK) 模型可以预测个体化给药的谷浓度。

客观的

本研究的目的是在患有 IBD 的儿科人群中开发英夫利昔单抗的 PopPK 模型，评估单核苷酸多态性 (SNP) 和其他生物标志物对英夫利昔单抗清除的影响。

方法

这项观察性、双向性单中心研究是在 2016 年 7 月至 2022 年 7 月期间在希伯伦山谷大学医院 (HUVH)（西班牙）儿科胃肠病科接受英夫利昔单抗治疗的 IBD 儿科患者中进行的。收集人口统计、临床和分析变量。分析了 20 个可能与英夫利昔单抗血浆浓度反应变化相关的 SNP。通过 ELISA 测定英夫利昔单抗血清浓度和英夫利昔单抗抗体 (ATI)。PopPK 建模是使用非线性混合效应分析 (NONMEM) 进行的。

结果

包括 30 名患者（21 名男性）。开始英夫利昔单抗治疗时的中位年龄（范围）为 13 岁（16 个月至 16 岁）。模型开发共获得 190 个样本（诱导阶段有 49 个样本 [25.8%]）。使用二室模型描述了英夫利昔单抗的药代动力学（PK）。体重、红细胞沉降率 (ESR)、粪便钙卫蛋白 (FC) 和 SNP rs1048610 ( ADAM17 ) 对清除率 (CL) 和白蛋白对室间清除率 (Q) 具有统计学意义。CL1（基因型 1-AA）、CL2（基因型 2-AG）、CL3（基因型 3-GG）、Q、V _c和V _p（中央和外周分布容积）的估计值为 0.0066 L/h/46.4 kg，分别为 0.0055 升/小时/46.4 千克、0.0081 升/小时/46.4 千克、0.0029 升/小时/46.4 千克、0.6750 升/46.4 千克和 1.19 升/46.4 千克。清除率、V _c和V _p的个体间变异性 (IIV) 估计值分别为 19.33、16.42 和 36.02%。

结论

利用体重、白蛋白、FC、ESR 和 SNP rs1048610 的 popPK 模型准确预测了 IBD 儿童的英夫利昔单抗谷浓度。