Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
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DOI：
10.1093/infdis/jiac024
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发表时间：
2022-02-25
影响因子：
6.4
通讯作者：
Brust, James C. M.
中科院分区：
文献类型：
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作者：
Haas, David W.;Abdelwahab, Mahmoud Tareq;Brust, James C. M.
在南非接受耐药结核病治疗的一组患者中，CYP3A5*3 与血浆贝达喹啉清除率减慢相关。人群中不同的 CYP3A5*3minor 等位基因频率可能有助于解释先前报道的非洲血统的贝达喹啉清除速度更快。背景 据报道，非洲血统的血浆贝达喹啉清除速度更快。我们的目的是确定遗传多态性是否可以解释南非一组接受耐药结核病治疗的患者中贝达喹啉、其 M2 代谢物和氯法齐明血浆清除率的个体差异。方法 用非线性混合效应模型估计血浆清除率。使用线性回归模型检查药物遗传学多态性、全基因组多态性和清除率变异性之间的关联。结果 在 195 名队列参与者中，有 140 名可进行遗传关联评估。在基于先前与任何药物的全基因组显着关联而选择的 21 个多态性中，rs776746 (CYP3A5*3) 与贝达奎林的较慢清除率相关 (P = .0017)，但与 M2 无关 (P = .25)。 CYP3A5*3 杂合性和纯合性分别与贝达喹啉清除速度减慢 15% 和 30% 相关。氯法齐明清除率的 P 值最低的是 VKORC1 rs9923231 (P = .13)。在全基因组分析中，贝达喹啉和氯法齐明清除率的最低 P 值分别为 RFX4 rs76345012 (P = 6.4 x 10(-7)) 和 CNTN5 rs75285763 (P = 2.9 x 10(-8))。结论 在接受耐药结核病治疗的南非人中，CYP3A5*3 与贝达喹啉清除率减慢相关。人群中不同的 CYP3A5*3 频率可能有助于解释非洲人报告的贝达喹啉清除速度更快的原因。与 RFX4 和 CNTN5 的关联可能纯属偶然。
In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5*3was associated with slower plasma bedaquiline clearance. Different CYP3A5*3minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.Background Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa. Methods Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models. Results Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5*3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5*3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 x 10(-7)) and CNTN5 rs75285763 (P = 2.9 x 10(-8)), respectively. Conclusions Among South Africans treated for drug-resistant tuberculosis, CYP3A5*3 was associated with slower bedaquiline clearance. Different CYP3A5*3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.