基于单中心的中国血液肿瘤患者维奈托克群体药动学模型的建立与应用

Establishment and Application of a Population Pharmacokinetic Model of Venetoclax in Chinese Patients with Hematological Malignancies Based on a Single-center Cohort

关键词:  维奈托克  群体药动力学  血液肿瘤

Key words:  venetoclax  population pharmacokinetics  hematological malignancies

摘要:

摘要：目的：基于单中心建立中国血液肿瘤患者维奈托克的群体药动学(Population pharmacokinetic, PPK )模型，并确定可以解释药代动力学（pharmacokinetic, PK）个体变异性的协变量，为维奈托克临床精准用药提供科学依据。方法：收集2021 年 6 月—2022 年 8 月在浙江大学医学院附属第一医院接受维奈托克治疗的血液肿瘤患者 122例，共465个血药浓度监测数据。采用非线性混合效应模型(NONMEM)构建模型，并考察年龄、性别、肝功能指标(ALT, AST, ALB)、肾功能指标(Scr, BUN, CLcr)、联合用药(CYP3A酶诱导剂/抑制剂)等协变量对维奈托克药动学参数的影响。结果： 维奈托克PPK特征符合一级吸收和消除的一室模型。群体典型表观清除率(CL/F)为9.65 L/h。CYP3A酶抑制剂联用、ALT升高和年龄增长显著降低维奈托克的CL/F。模型评价表明该模型具有良好的拟合性、稳定性和可靠性。模型仿真显示，在相同给药方案下，联用CYP3A酶抑制剂、高龄及ALT升高患者维奈托克暴露量显著增加。外部数据集结果进一步表明所建立的PPK模型具备潜在的临床适用性。结论：成功建立了稳定可靠的中国血液肿瘤患者维奈托克PPK模型。CYP3A酶抑制剂联用、高龄及ALT升高是降低CL/F、增加暴露的关键因素。该模型可为基于患者个体特征的维奈托克精准给药提供科学依据。

Abstract:

Abstract: Objective To establish a population pharmacokinetic (PPK) model of venetoclax in Chinese patients with hematological malignancies based on a single-center cohort, identify covariates that explain the interindividual variability in pharmacokinetics (PK), and provide a scientific basis for the clinical precision medication of venetoclax.. Methods A total of 122 patients with hematological malignancies who received venetoclax treatment at the First Affiliated Hospital of Zhejiang University School of Medicine from June 2021 to August 2022 were enrolled, and 465 plasma concentration monitoring data points were collected. A nonlinear mixed-effects model (NONMEM) was used to construct the PPK model. The effects of covariates, including age, gender, liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin [ALB]), renal function indicators (serum creatinine [Scr], blood urea nitrogen [BUN], creatinine clearance [CLcr]), and concomitant medications (CYP3A enzyme inducers/inhibitors), on the pharmacokinetic parameters of venetoclax were investigated. Results The PPK characteristics of venetoclax were consistent with a one-compartment model with first-order absorption and elimination. The typical population apparent clearance (CL/F) of venetoclax was 9.65 L/h. Concomitant use of CYP3A enzyme inhibitors, increased ALT levels, and advanced age significantly decreased the CL/F of venetoclax. Model evaluation demonstrated that the established model had good fitting performance, stability, and reliability. Model simulation showed that under the same dosage regimen, the exposure of venetoclax was significantly increased in patients with concomitant use of CYP3A enzyme inhibitors, advanced age, or elevated ALT levels. Furthermore, the results of the external dataset further indicate that the established PPK model has potential clinical applicability. Conclusion A stable and reliable PPK model of venetoclax in Chinese patients with hematological malignancies was successfully established. Concomitant use of CYP3A enzyme inhibitors, advanced age, and elevated ALT levels are key factors that reduce CL/F and increase the exposure of venetoclax. This model can provide a scientific basis for the precision dosage adjustment of venetoclax based on individual patient characteristics.