目的:已报道异烟肼在不同人群中的药代动力学差异显著。我们旨在总结异烟肼在结核病(TB)患者中的群体药代动力学研究,重点关注N-乙酰转移酶2(NAT2)基因型/单核苷酸多态性(SNP)对异烟肼清除的影响。
方法:在PubMed和Embase中进行了系统搜索,以确定异烟肼的群体药代动力学(PopPK)研究。如果患者人群患有结核病并接受异烟肼治疗,非线性混合效应建模,和参数方法用于建立异烟肼PopPK模型,并测试NAT2基因型/SNP作为模型开发的协变量。
结果:共有12篇文章来自PubMed,Embase,手搜索文章。在大多数研究中,使用具有一阶吸收和线性消除的两室模型描述了异烟肼的分布。影响异烟肼药代动力学的重要协变量是NAT2基因型,体重,瘦体重,身体质量指数,无脂质量,efavirenz,配方,CD4细胞计数,和性别。在成人结核病人群中进行的大多数研究报告,与慢速乙酰化剂相比,NAT2快速乙酰化剂的异烟肼清除率增加了两倍或三倍。
结论:异烟肼的易变性主要归因于NAT2基因型。这导致三峰清除模式,与缓慢的乙酰化剂相比,NAT2快速乙酰化剂的清除增加了多倍。需要进一步研究探索开发的PopPK模型在不同临床环境中的普遍性/适应性。
OBJECTIVE: Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 (NAT2) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid.
METHODS: A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development.
RESULTS: A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators.
CONCLUSIONS: The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.