基因型指导的中国系统性红斑狼疮患者羟氯喹给药剂量优化新方法。

Genotype-guided new approach for dose optimisation of hydroxychloroquine administration in Chinese patients with SLE.

作者信息

Xie Han, Wen Xin, Wang Yuchun, Huang Xuan, Shu Qing, Wang Dandan, Geng Linyu, Jin Ziyi, Shen Wei, Ge Weihong, Zhu Yizhun, Sun Lingyun

机构信息

School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China.

Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province, China.

出版信息

Lupus Sci Med. 2023 Nov 22;10(2):e000997. doi: 10.1136/lupus-2023-000997.

DOI:10.1136/lupus-2023-000997

PMID:37993281

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10668244/

Abstract

OBJECTIVES

The study aims to investigate the impact of gene polymorphisms on blood hydroxychloroquine (HCQ) concentrations in patients with SLE and provide guidelines for individualised care.

METHODS

489 Chinese patients with SLE taking HCQ for more than 3 months were collected in this study. The blood HCQ, desethylhydroxychloroquine (DHCQ) and desethylchloroquine concentrations were measured. The optimal blood concentration of HCQ was determined by receiver operating characteristic curve analysis. Single nucleotide polymorphisms of metabolic enzymes involved in HCQ metabolism were genotyped and the associations with treatment effects were investigated.

RESULTS

The cut-off value of HCQ was 559.67 ng/mL, with sensitivity and specificity values of 0.51 and 0.89, respectively. The TC and CC genotypes of CYP2C8 (rs7910936) were significantly related to the increase in blood HCQ concentrations, and the CYP2C8 (rs10882521) TT genotype was associated with lower blood HCQ concentrations. The DHCQ:HCQ ratio was highest in patients with the GG genotype of the CYP2D610 (rs1065852) polymorphism and lowest in those with the AA genotype. Patients with the CYP2C8 (rs7910936) CC genotype were more likely to achieve the optimal blood concentration (p=0.030) in HCQ 200 mg/day group and patients with the CYP2D610 (rs1065852) GG genotype were more likely to reach the optimal blood concentration (p=0.049) in 400 mg/day group.

CONCLUSIONS

Our results suggest that the optimal blood concentration of HCQ measured approximately 12-18 hours after the last dosage may be between 500 and 600 ng/mL in Chinese patients with SLE. The observed variations in HCQ concentrations between individuals can potentially be attributed to genetic polymorphisms in CYP2D6*10 (rs1065852) and CYP2C8 (rs7910936 and rs10882521). Genotypical testing of patients and regular monitoring of blood levels are recommended for optimising HCQ dosage management in Chinese patients with SLE.

TRIAL REGISTRATION NUMBER

ChiCTR2300070628.

摘要

目的

本研究旨在探讨基因多态性对系统性红斑狼疮（SLE）患者血液中羟氯喹（HCQ）浓度的影响，并为个体化治疗提供指导。

方法

本研究收集了489例服用HCQ超过3个月的中国SLE患者。检测血液中HCQ、去乙基羟氯喹（DHCQ）和去乙基氯喹的浓度。通过受试者工作特征曲线分析确定HCQ的最佳血药浓度。对参与HCQ代谢的代谢酶的单核苷酸多态性进行基因分型，并研究其与治疗效果的相关性。

结果

HCQ的截断值为559.67 ng/mL，敏感性和特异性值分别为0.51和0.89。CYP2C8（rs7910936）的TC和CC基因型与血液中HCQ浓度升高显著相关，CYP2C8（rs10882521）的TT基因型与血液中HCQ浓度降低相关。CYP2D610（rs1065852）多态性的GG基因型患者的DHCQ:HCQ比值最高，AA基因型患者的比值最低。CYP2C8（rs7910936）CC基因型的患者在每日服用200 mg HCQ组中更有可能达到最佳血药浓度（p = 0.030），而CYP2D610（rs1065852）GG基因型的患者在每日服用400 mg组中更有可能达到最佳血药浓度（p = 0.049）。

结论

我们的研究结果表明，对于中国SLE患者，末次给药后约12 - 18小时测得的HCQ最佳血药浓度可能在500至600 ng/mL之间。个体间观察到的HCQ浓度差异可能归因于CYP2D6*10（rs1065852）和CYP2C8（rs7910936和rs10882521）的基因多态性。建议对患者进行基因分型检测并定期监测血药水平，以优化中国SLE患者的HCQ剂量管理。