Laboratory of Pharmacology, Pharmacogenetics and Toxicology, Grenoble Alpes University Hospital, Grenoble, France.
Univ. Grenoble Alpes, HP2 INSERM U1300, 38041, Grenoble, France.
BioDrugs. 2024 Sep;38(5):703-716. doi: 10.1007/s40259-024-00676-z. Epub 2024 Aug 15.
Tocilizumab prevents the clinical worsening of chronic active antibody-mediated rejection (CAAMR) in kidney transplant recipients. Following a global shortage of the intravenous pharmaceutical form in 2022, patients were switched from monthly intravenous administration of 8 mg/kg to weekly subcutaneous injection of 162 mg, raising the question of bioequivalence between these schemes of administration.
We aimed to compare the areas under the curve (AUC) of tocilizumab in virtual simulations of populations treated with the two administration schemes and to identify the covariates that could contribute to pharmacokinetic variability of tocilizumab in kidney transplant patients with CAAMR who received tocilizumab as salvage treatment.
This retrospective monocentric study included 43 kidney transplant patients (202 tocilizumab concentrations) with CAAMR treated with intravenous or subcutaneous tocilizumab between December 2020 and January 2023. We developed a population pharmacokinetic model using nonlinear mixed effects modeling and identified the covariates that could contribute to tocilizumab AUC variability. Monte Carlo simulations were then performed to assess the subcutaneous and intravenous tocilizumab AUC for 0-28 days (M1), 56-84 days (M3), 140-168 days (M6), and 308-336 days (M12). Bioequivalence was defined by SC/IV AUC geometric mean ratios (GMRs) between 0.80 and 1.25.
A two-compartment model with parallel linear and nonlinear elimination best described the concentration-time data. Significant covariates for tocilizumab clearance were body weight, urinary albumin-to-creatinine ratio (ACR), and inflammation status [C-reactive protein (CRP) ≥ 5 mg/L]. The GMR values and their 90% confidence intervals at M3, M6, and M12 were within the 0.8-1.25 margin for equivalence. Conversely, the 90% prediction intervals of the GMR were much wider than the 90% confidence intervals and did not fall within 0.8 and 1.25.
From month 3 of treatment, the subcutaneous and intravenous tocilizumab administration schemes provided average bioequivalent pharmacokinetic exposure at the population level but not at the individual level. Body weight, inflammation, ACR, and administration scheme should be considered to personalize the dose of tocilizumab for patients with CAAMR. Further studies are required to determine the target of tocilizumab exposure in kidney transplant patients with CAAMR.
托珠单抗可预防慢性活动性抗体介导的排斥反应（CAAMR）患者的临床恶化。2022 年，全球静脉注射药物短缺后，患者从每月静脉注射 8mg/kg 改为每周皮下注射 162mg，这引发了两种给药方案之间是否生物等效的问题。
我们旨在比较人群中虚拟模拟的两种给药方案的托珠单抗曲线下面积（AUC），并确定可能导致 CAAMR 肾移植患者接受托珠单抗作为挽救治疗时托珠单抗药代动力学变异性的协变量。
本回顾性单中心研究纳入了 2020 年 12 月至 2023 年 1 月期间接受静脉或皮下托珠单抗治疗的 43 例 CAAMR 肾移植患者（202 个托珠单抗浓度）。我们使用非线性混合效应模型建立了群体药代动力学模型，并确定了可能导致托珠单抗 AUC 变异性的协变量。然后进行蒙特卡罗模拟，以评估 0-28 天（M1）、56-84 天（M3）、140-168 天（M6）和 308-336 天（M12）时的皮下和静脉托珠单抗 AUC。生物等效性定义为 SC/IV AUC 几何均数比值（GMR）在 0.80 到 1.25 之间。
平行线性和非线性消除的两室模型最能描述浓度-时间数据。托珠单抗清除率的显著协变量为体重、尿白蛋白/肌酐比值（ACR）和炎症状态[C 反应蛋白（CRP）≥5mg/L]。M3、M6 和 M12 时 GMR 值及其 90%置信区间在等效性的 0.8-1.25 范围内。相反，GMR 的 90%预测区间比 90%置信区间宽得多，并且不在 0.8 和 1.25 之间。
从治疗的第 3 个月开始，皮下和静脉托珠单抗给药方案在人群水平上提供了平均生物等效的药代动力学暴露，但在个体水平上没有。体重、炎症、ACR 和给药方案应考虑用于 CAAMR 患者的托珠单抗剂量个体化。需要进一步研究以确定 CAAMR 肾移植患者的托珠单抗暴露目标。
