Effect of drug metabolism gene polymorphisms on blood concentration and safety of tacrolimus in children with refractory nephrotic syndrome
10.3760/cma.j.cn114015-20220407-00293
- VernacularTitle:药物代谢相关基因多态性对难治性肾病患儿他克莫司血药浓度及安全性的影响
- Author:
Shujuan ZHEN
1
;
Jianjiang ZHANG
;
Huiqin ZENG
;
Qin WANG
;
Mengmeng JIA
Author Information
1. 郑州大学第一附属医院儿科，郑州 450052
- Publication Type:Journal Article
- Keywords:
Nephrotic syndrome;
Nephrosis;
Genotype;
Child;
Tacrolimus
- From:
Adverse Drug Reactions Journal
2022;24(10):515-521
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the effect of drug metabolism gene polymorphisms on blood concentration and safety of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS).Methods:The study was designed as prospective observational clinical study. The subjects were selected from the children with RNS who were hospitalized in Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from September 1, 2018 to August 31, 2019 and planned to receive TAC (first application) at the basis of glucocorticoids treatment. Clinical research files were formed and clinical conditions within 6 months of TAC treatment were recorded in detail for all subjects. The peripheral venous blood of all children was collected on the 7th day after TAC application for TAC blood trough concentration detection, and the TAC dose was adjusted according to the results. Blood samples were collected at the right time during hospitalization and gene polymorphisms of adenosine triphosphate binding cassette transporter B1 (ABCB1), cytochrome P450 (CYP) 2C19, CYP3A4, CYP3A5 and nuclear receptor subfamily 1, group I, member 2 (NR1I2) were detected. Children who completed 6 months of TAC treatment and follow-up were included. According to the genotype detection results, children were divided into wild-type group, heterozygous mutant group, and homozygous mutant group and first dose-adjusted blood trough concentration (C/D) of TAC were compared; they were divided into mutation carrier group (including heterozygous mutation carriers and homozygous mutation carriers) and wild-type group and the incidence of adverse reactions were compared.Results:A total of 39 children were included in the analysis, including 24 males and 15 females, aged 3 to 13 years with a median age of 8 years. The comparison results of the first C/D of TAC among various genotype groups showed that the TAC C/D in children of CYP2C19 homozygous mutant (*2*2) group was higher than that of wild-type (*1*1) group [3.65 (2.78, 7.43) μg/L vs. 1.53 (1.27, 3.33) μg/L, P=0.032], TAC C/D in children of CYP3A5 homozygous mutant (*3*3) group was significantly higher than those of the wild-type (*1*1) group and heterozygous mutation (*1*3) group [3.68 (3.05, 5.14) μg/L vs. 2.10 (0.77, 3.56) μg/L and 1.74 (1.47, 3.25) μg/L, P=0.046, P=0.009], and no significant differences were found in TAC C/D among different genotypes in CYP3A4, ABCB1, or NR1I2 (all P>0.05). A total of 7 children had adverse reactions within 6 months of TAC treatment (Naranjo′s assessment scale, "probable" in 2 children and "possible" in 5 children), including infection, rash, hypertensive encephalopathy, and convulsions in 4, 1, 1, 1 child, respectively. The incidence of adverse reactions in ABCB1 mutation carrying children (CT and TT) was significantly higher than that in children of wild-type (CC) group [30.4% (7/23) vs. 0 (0/16), P=0.033]. Conclusion:CYP2C19 and CYP3A5 gene polymorphisms have significant effects on TAC blood concentration, and ABCB1 gene polymorphisms have significant effects on the safety of TAC application, which should be noticed in clinic.
