Factors influencing methotrexate and methotrexate polyglutamate in patients with rheumatoid arthritis: a systematic review of population pharmacokinetics

Q2 Pharmacology, Toxicology and Pharmaceutics Drug metabolism and personalized therapy Pub Date : 2022-02-24 DOI:10.1515/dmpt-2021-0190

Janthima Methaneethorn, Rowan Alejielat, Nattawut Leelakanok

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Abstract

Abstract Low dose methotrexate (MTX) is commonly used in the treatment of rheumatoid arthritis. The clinical effect is mediated by its metabolite, methotrexate polyglutamate (MTX-PGn). The drug exhibits high interindividual pharmacokinetic variability and the optimal MTX dose is different among individuals. Thus, several MTX population pharmacokinetic (PopPK) models were developed to characterize factors affecting MTX pharmacokinetic variability. This review summarizes significant predictors for MTX pharmacokinetics and identifies knowledge gaps to be further examined. A total of 359 articles were identified from a systematic search of four databases: PubMed, Science Direct, and CINAHL Complete. Of these eight studies were included. Most studies investigated influential factors on MTX pharmacokinetics, but information on MTX-PGn is limited, with only one study performing a parent-metabolite (MTX-PG3) model. MTX pharmacokinetics was described using a two-compartment model with first-order elimination in most studies, with the MTX clearance ranging from 6.94 to 12.39 L/h. Significant predictors influencing MTX clearance included weight, creatinine clearance, sex, OATP1B3 polymorphism, and MTX multiple dosing. While body mass index and red blood cell counts were significant predictors for MTX-PG3 clearance. Providing that MTX-PGn plays a crucial role in clinical effect, further studies should determine other factors affecting MTX-PGn as well as its relationship with clinical response.

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类风湿关节炎患者甲氨蝶呤和甲氨蝶呤聚谷氨酸的影响因素:人群药代动力学的系统综述

摘要低剂量甲氨蝶呤(MTX)是治疗类风湿性关节炎的常用药物。临床效果是由其代谢物甲氨蝶呤聚谷氨酸(MTX-PGn)介导的。药物表现出高度的个体间药代动力学变异性，最佳MTX剂量在个体之间是不同的。因此，开发了几个MTX群体药代动力学(PopPK)模型来表征影响MTX药代动力学变异性的因素。这篇综述总结了MTX药代动力学的重要预测因素，并确定了有待进一步研究的知识空白。系统检索PubMed、Science Direct和CINAHL Complete四个数据库，共发现359篇文章。纳入了这8项研究。大多数研究调查了MTX药代动力学的影响因素，但关于MTX- pgn的信息有限，只有一项研究采用了母体代谢物(MTX- pg3)模型。大多数研究采用一阶消除的双室模型描述MTX药代动力学，MTX清除率范围为6.94 ~ 12.39 L/h。影响MTX清除率的重要预测因素包括体重、肌酐清除率、性别、OATP1B3多态性和MTX多次给药。而体重指数和红细胞计数是MTX-PG3清除率的重要预测因子。鉴于MTX-PGn在临床疗效中起着至关重要的作用，进一步的研究应确定影响MTX-PGn的其他因素及其与临床反应的关系。

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来源期刊

Drug metabolism and personalized therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

2.30

自引率

0.00%

发文量

期刊介绍： Drug Metabolism and Personalized Therapy (DMPT) is a peer-reviewed journal, and is abstracted/indexed in relevant major Abstracting Services. It provides up-to-date research articles, reviews and opinion papers in the wide field of drug metabolism research, covering established, new and potential drugs, environmentally toxic chemicals, the mechanisms by which drugs may interact with each other and with biological systems, and the pharmacological and toxicological consequences of these interactions and drug metabolism and excretion. Topics: drug metabolizing enzymes, pharmacogenetics and pharmacogenomics, biochemical pharmacology, molecular pathology, clinical pharmacology, pharmacokinetics and drug-drug interactions, immunopharmacology, neuropsychopharmacology.