成人患者中达托霉素群体药代动力学模型的系统评价与研究进展

Systematic Review and Research Progress of Population Pharmacokinetic Models of Daptomycin in Adults

关键词:  达托霉素，群体药代动力学，系统综述，非线性混合效应模型，个体化药物治疗

Key words:  Daptomycin  population pharmacokinetic  systematic review  nonlinear mixed effect model  personalized medicine.

摘要:

目的 达托霉素的药代动力学存在显著个体间变异，仅依据体重调整难以实现精准给药。本研究旨在系统评价已发表的达托霉素群体药代动力学（population pharmacokinetic, PopPK）模型，总结模型结构、协变量及验证方法，识别影响药代动力学变异的关键因素，为特殊人群的个体化给药提供理论依据。方法 计算机检索PubMed、Embase、Cochrane Library、Web of Science、CNKI、万方和维普等数据库，检索时限从建库至2025年9月4日。由两名研究者独立筛选文献并提取数据，纳入符合标准的成年患者达托霉素PopPK研究，提取相关数据进行分析。结果 共纳入24项研究。多数研究采用NONMEM软件（15项）进行建模，模型多为二室模型（18项）。达托霉素清除率（clearance, CL）典型值范围为0.229–1.02 L/h，中央室分布容积（volume of central compartment, Vc）为3.59–151 L。CL的主要协变量为肾功能（肌酐清除率或肾小球滤过率）和体重；Vc的主要协变量包括体重、性别、体成分（如去脂体重）和疾病状态。模型多通过Bootstrap、视觉预测检查等方法进行验证。结论 肾功能、体重和疾病状态是达托霉素的药代动力学变异的主要原因，对于肾功能不全、肥胖、重症等特殊人群的需要采用适宜的模型进行个体化方案制定。未来需扩大样本量、加强多中心验证，并进一步探索特殊人群及遗传因素对药代行为的影响。

Abstract:

Objective: The pharmacokinetics of daptomycin shows significant inter-individual variation, and precise dosing is difficult to achieve by adjusting based on body weight only. This study aimed to systematically evaluate published population pharmacokinetic (PopPK) models of daptomycin regarding their structural characteristics, covariate effects, and validation strategies, and identify key factor that affect its pharmacokinetics, and to provide evidence for individualized therapy. Methods: A comprehensive literature search was performed in PubMed, Web of Science, Embase, Cochrane Library, CNKI, WanFang, and VIP databases from inception until September 4, 2025. Two investigators independently screened studies and extracted data from eligible PopPK studies of daptomycin in adults. Results: Twenty-four studies were included. The two-compartment model (n=18) and NONMEM software (n=15) were most frequently used. Typical population estimates for clearance (CL) and central volume of distribution (Vc) ranged from 0.229 to 1.02 L/h and 3.59 to 151 L, respectively. Renal function and body weight were the primary covariates for CL, while Vc was significantly associated with body weight, sex, body composition, and disease status. Bootstrap and visual predictive check were common validation methods. Conclusion: Daptomycin are most commonly affected by renal impairment, obesity and critical illness. Patients with these factors should be dosed based on suitable PopPK models. Future efforts should focus on larger, prospective multi-center studies, external validation, and investigating factors in underrepresented populations to refine precision dosing.