在复发/难治性弥漫性大B细胞淋巴瘤（DLBCL）患者中，营救化疗方案（例如利妥昔单抗、异环磷酰胺、卡铂和依托泊苷，R-ICE）的效果较差。卡替佐米是一种不可逆的蛋白酶体抑制剂，可以克服获得性利妥昔单抗化疗耐药性，并且与R-ICE联合应用可以改善R/R DLBCL患者的疗效。本分析旨在为R/R DLBCL患者的卡替佐米进行种群药代动力学/药效学（PK/PD）模型的开发。 在一项单中心、开放标签、前瞻性1期研究中，患者在每21天内的第1、2、8和9天接受卡替佐米（10、15或20 mg/m2）以及标准剂量的R-ICE（第3-6天，最多三个周期）。利用液相色谱串联质谱法测量了卡替佐米的血浆浓度，持续时间为输注后的24小时。利用稀疏采样评估了外周血单个核细胞中的蛋白酶体活性（PD生物标志物）在第1-2天进行了评估。使用NONMEM v7.4.1与Finch Studio v1.1.0和PsN v4.7.0进行了PK/PD模型的开发。模型选择依据客观函数值、适应度和可视化预测检验进行。使用逐步协变量建模进行协变量选择。 28名患者参与了PK/PD分析，共纳入了217个PK样本和127个PD样本。卡替佐米的PK最佳描述为两室模型，具有线性排泄特征（典型总清除率为133 L/h）。蛋白酶体活性最好用具有不可逆失活的转座模型来描述。所有参数的估计精度良好。未发现具有统计学意义的协变量。 成功开发了验证的基于人群的卡替佐米PK/PD模型。需要进一步研究卡替佐米与R-ICE联合治疗的反应变异性来源。 ClinicalTrials.gov标识号NCT01959698。 © 2023. 作者，独家授权于Springer Nature Switzerland AG。

In patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), salvage chemotherapy regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide, R-ICE) yield poor outcomes. Carfilzomib, an irreversible proteasome inhibitor, can overcome acquired rituximab-chemotherapy resistance and, when combined with R-ICE, improves outcomes in patients with R/R DLBCL.This analysis aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for carfilzomib in R/R DLBCL patients.In a single-center, open-label, prospective phase 1 study, patients received carfilzomib (10, 15, or 20 mg/m2) on days 1, 2, 8, and 9, and standard doses of R-ICE on days 3-6 every 21 days (maximum of three cycles). Carfilzomib plasma concentrations up to 24 h postinfusion were measured by liquid chromatography coupled with tandem mass spectrometry. Proteasome activity (PD biomarker) in peripheral blood mononuclear cells was assessed on days 1-2 with sparse sampling. PK/PD models were developed using NONMEM v7.4.1 interfaced with Finch Studio v1.1.0 and PsN v4.7.0. Model selection was guided by objective function value, goodness-of-fit, and visual predictive checks. Stepwise covariate modeling was used for covariate selection.Twenty-eight patients were enrolled in the PK/PD analysis, from whom 217 PK samples and 127 PD samples were included. Carfilzomib PK was best described by a two-compartment model with linear disposition (typical total clearance of 133 L/h). Proteasome activity was best characterized using a turnover model with irreversible inactivation. All parameters were estimated with good precision. No statistically significant covariates were identified.A validated population-based PK/PD model of carfilzomib was developed successfully. Further research is needed to identify sources of variability in response to treatment with carfilzomib in combination with R-ICE.ClinicalTrials.gov identifier number NCT01959698.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.