High plasma concentration of tenofovir alafenamide in people living with HIV with ABCB1 genetic variants.

IF 1.9 4区 医学 Q3 INFECTIOUS DISEASES Journal of Infection and Chemotherapy Pub Date : 2024-10-18 DOI:10.1016/j.jiac.2024.10.009
Kiyoto Tsuchiya, Hieu Trung Tran, Akira Kawashima, Koji Watanabe, Akinobu Hamada, Shinichi Oka, Hiroyuki Gatanaga
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Abstract

Objectives: We aimed to analyze the relationships between single nucleotide polymorphisms in the ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2) genes and plasma concentrations of tenofovir alafenamide (TAF), tenofovir (TFV), and emtricitabine (FTC).

Methods: We recruited 10 people living with HIV receiving once-daily treatment with a single tablet containing TAF (25 mg), FTC (200 mg), and bictegravir (50 mg). Peripheral blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. Plasma concentrations of TAF, TFV, and FTC were quantified using liquid chromatography-tandem mass spectrometry. Genotyping for allelic variants of ABCB1, including 1236C > T (rs1128503), 2677 G > T/A (rs2032582), 3435C > T (rs1045642), 4036 A > G (rs3842) and ABCG2 421C > A (rs2231142), was performed using TaqMan Drug Metabolism Assays.

Results: None of the genotypes for ABCB1 1236C > T, 2677 G > T/A, 3435C > T, and ABCG2 421C > A exhibited correlations with plasma concentrations of TAF, TFV, and FTC. In contrast, individuals with the ABCB1 4036 AG genotype (188.7 ng/mL, n = 3) exhibited a significantly higher mean peak plasma concentration of TAF than those with the ABCB1 4036 AA genotype (67.7 ng/mL, n = 7) (p = 0.0167). However, these genotypes did not affect the elimination of terminal half-lives of TAF.

Conclusions: The allelic variant ABCB1 4036 A > G is associated with reduced protein expression and function of ABCB1. Individuals with this genetic variant exhibited significantly high peak plasma concentrations of TAF, potentially due to the reduced expression of efflux transporters in the intestines linked to this variant.

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具有 ABCB1 基因变异的 HIV 感染者体内替诺福韦-阿拉非那胺的血浆浓度较高。
研究目的我们旨在分析ATP结合盒转运体B1(ABCB1)和G2(ABCG2)基因的单核苷酸多态性与替诺福韦-阿拉非那胺(TAF)、替诺福韦(TFV)和恩曲他滨(FTC)血浆浓度之间的关系:我们招募了 10 名艾滋病病毒感染者,他们每天接受一次含 TAF(25 毫克)、FTC(200 毫克)和 bictegravir(50 毫克)的片剂治疗。在服药后 0、1、2、3、4、6、8、12 和 24 小时采集外周血样本。采用液相色谱-串联质谱法对血浆中 TAF、TFV 和 FTC 的浓度进行定量。使用 TaqMan 药物代谢测定法对 ABCB1 的等位基因变异进行了基因分型,包括 1236 C>T (rs1128503)、2677 G>T/A (rs2032582)、3435 C>T (rs1045642)、4036 A>G (rs3842) 和 ABCG2 421 C>A (rs2231142):结果:ABCB1 1236 C>T、2677 G>T/A、3435 C>T和ABCG2 421 C>A的基因型均与TAF、TFV和FTC的血浆浓度无关。相比之下,ABCB1 4036 AG 基因型个体(188.7 纳克/毫升,n = 3)的 TAF 平均血浆峰值浓度明显高于 ABCB1 4036 AA 基因型个体(67.7 纳克/毫升,n = 7)(p = 0.0167)。然而,这些基因型并不影响 TAF 末端半衰期的消除:结论:等位基因变体 ABCB1 4036 A>G 与 ABCB1 蛋白表达和功能降低有关。具有该基因变异的个体血浆中 TAF 的峰值浓度明显较高,这可能是由于与该变异相关的肠道中外排转运体的表达减少所致。
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来源期刊
Journal of Infection and Chemotherapy
Journal of Infection and Chemotherapy INFECTIOUS DISEASES-PHARMACOLOGY & PHARMACY
CiteScore
4.10
自引率
4.50%
发文量
303
审稿时长
47 days
期刊介绍: The Journal of Infection and Chemotherapy (JIC) — official journal of the Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases — welcomes original papers, laboratory or clinical, as well as case reports, notes, committee reports, surveillance and guidelines from all parts of the world on all aspects of chemotherapy, covering the pathogenesis, diagnosis, treatment, and control of infection, including treatment with anticancer drugs. Experimental studies on animal models and pharmacokinetics, and reports on epidemiology and clinical trials are particularly welcome.
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