我们旨在表征维多珠单抗在接受异基因造血干细胞移植(allo-HSCT)的成人急性移植物抗宿主疾病预防中的群体药代动力学(PK),并评估潜在的临床相关协变量。给药,患者特征,从1b阶段开始PK,开放标签,在接受allo-HSCT的患者中,维多珠单抗75mg初始剂量递增至300mg的剂量发现研究和维多珠单抗300mg的3期研究使用具有线性消除的两室群体PK模型进行分析.协变量包括年龄,种族,体重,性别,白蛋白,淋巴细胞计数,GvHD类型,和伴随的药物。重量,白蛋白,和淋巴细胞计数是随时间变化的协变量。模型选择是由拟合优度标准驱动的,参数估计的精度,和视觉预测检查。在193名接受allo-HSCT的患者中,维多珠单抗PK由两室描述,线性PK模型。使用参考协变量值,最终参数估计(95%置信区间[CI])为:清除率,0.148(0.136,0.162)升/天;集中配送量,3.12(3.03,3.21)L;室间间隙,0.500(0.408,0.612)L/天;和外周分布量,3.95(3.52,4.44)L。体重和白蛋白是维多珠单抗PK的最重要预测因子,低体重/高白蛋白的清除率降低约20%,高体重/低白蛋白的清除率增加约30%。维多珠单抗清除率与年龄呈负相关,但对淋巴细胞计数或GvHD型没有检测到的影响。事后分析未检测到维多珠单抗PK与合并用药之间的任何关系。总之,所研究的协变量对维多珠单抗的PK没有临床意义的影响.
We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.