Metrum Research Group, Tariffville, Connecticut, USA.
Takeda Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
Pharmacol Res Perspect. 2024 Oct;12(5):e1257. doi: 10.1002/prp2.1257.
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.
我们旨在描述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病预防用维得利珠单抗的群体药代动力学（PK），并评估潜在的临床相关协变量。使用两室群体 PK 模型分析来自维得利珠单抗 75mg 初始剂量递增至 300mg 的 1b 期开放标签剂量发现研究和 allo-HSCT 患者中维得利珠单抗 300mg 的 3 期研究的给药、患者特征和 PK 数据，该模型具有线性消除。协变量包括年龄、种族、体重、性别、白蛋白、淋巴细胞计数、GVHD 类型和伴随药物。体重、白蛋白和淋巴细胞计数是随时间变化的协变量。模型选择取决于拟合优度标准、参数估计的精度和可视化预测检查。在 193 名接受 allo-HSCT 的患者中，维得利珠单抗 PK 被很好地描述为两室线性 PK 模型。使用参考协变量值，最终参数估计值（95%置信区间[CI]）为：清除率，0.148（0.136，0.162）L/天；中央分布容积，3.12（3.03，3.21）L；隔室间清除率，0.500（0.408，0.612）L/天；外周分布容积，3.95（3.52，4.44）L。体重和白蛋白是维得利珠单抗 PK 的最重要预测因子，体重低/白蛋白高时清除率下降约 20%，体重高/白蛋白低时清除率增加约 30%。维得利珠单抗清除率与年龄呈反比关系，但淋巴细胞计数或 GVHD 类型无明显影响。事后分析未发现维得利珠单抗 PK 与伴随药物之间存在任何关系。总之，所研究的协变量对维得利珠单抗的 PK 没有临床意义的影响。
