Population Pharmacokinetics and Pharmacodynamics Modeling for the Use of Recaticimab in Healthy Volunteers and Patients with Hypercholesterolemia.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2025-06-30 DOI:10.1007/s40262-025-01512-5

Chang Shu, Ying Wang, Sheng Feng, Shengxian Yang, Kai Shen

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引用次数: 0

Abstract

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C from circulation. By inhibiting PCSK9, it is possible to provide early intervention to achieve clinical benefits.

Methods: The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model.

Results: A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates.

Discussion: No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy.

Trial registration: NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.

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健康志愿者和高胆固醇血症患者使用雷卡替单抗的人群药代动力学和药效学建模

蛋白转化酶枯草杆菌素/克辛9型（PCSK9）是一种由肝脏分泌的蛋白质，与低密度脂蛋白（LDL）受体结合，导致肝脏清除循环中LDL- c的能力下降。通过抑制PCSK9，可以提供早期干预以获得临床益处。方法：采用7项临床研究数据建立数据库，采用非线性混合效应分析软件NONMEM进行群体药代动力学/药效学（PopPK/PD）和PK/PD分析。模型的参数估计采用一阶相互作用条件估计（fce - i）方法。采用逐步协变量法（SCM）建立并评价最终模型。结果：建立了靶介导的药物处置模型（TMDD）模型和间接反应模型来描述recatiimab的PopPK谱和PK/PD谱。PopPK最终模型被描述为带有组合残差模型的单室TMDD模型。将PopPK/PD最终模型描述为带有加性残差模型的间接响应模型。体重、体重指数、年龄、他汀类药物治疗和性别作为显著协变量引入模型。讨论：不需要根据PopPK和PopPK/PD协变量调整临床剂量。估计肾小球滤过率和抗药物抗体对任何PopPK参数都不是显著的协变量。在达到稳定状态后，改变给药方案和延长给药间隔不应引起对药物疗效的担忧。试验注册号：NCT03634436、NCT03944109、NCT05370950、NCT04455581、NCT04849000、NCT04885218、NCT04844125。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.