Mackay Elizabeth, Platt Gareth, Peloquin Charles A, Brooks Meredith B, Coit Julia M, Velásquez Gustavo E, Pertinez Henry, Vargas Dante, Sánchez Epifanio, Calderón Roger I, Jiménez Judith, Tintaya Karen, Garcia Dalicxa, Osso Elna, Lecca Leo, Mitnick Carole, Davies Geraint R
Department of Clinical Infection, Microbiology and immunology, University of Liverpool, Liverpool, United Kingdom.
Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA.
J Infect Dis. 2025 Aug 14;232(2):e258-e265. doi: 10.1093/infdis/jiaf195.
Variability in the pharmacokinetics (PK) of first-line antituberculosis drugs (rifampicin [RIF], isoniazid [INH], and pyrazinamide [PZA]) is high and may be influenced by pharmacogenetic polymorphism. We performed a pharmacogenetic substudy in 90 participants with PK data from the HIRIF trial in Peru.
Relevant single-nucleotide polymorphisms (SNPs) in the NAT2, SLCO1B1, AADAC, and AOX1 loci were genotyped using real-time polymerase chain reaction (PCR).
The proportions of slow, intermediate, and fast acetylators predicted by a conventional 6-SNP NAT2 panel were 32.5%, 48.2%, and 19.2%, respectively. A single NAT2 tag SNP (rs1495741) agreed with the panel-predicted phenotype in 91% and was a better predictor of INH area under the curve (AUC). Accounting for discrepancies possibly caused by rare alleles not represented in the panel or that could be unequivocally resolved using observed AUC, sensitivity of the tag SNP was 97.7%. A previously described SNP in SLCO1B1 (rs4149032) was present at an allele frequency of 0.31 and appeared to influence RIF AUC and maximum concentration (Cmax) at a dose of 20 mg/kg, despite an extreme distribution of alleles across the randomized arms. The AADAC SNP (rs1803155) predominated in the study population and was not linked to RIF PK, although an effect could have been missed due to sample size and allele frequency. There was no association between PZA PK and a common SNP in AOX1 (rs55754655).
A tag SNP approach may offer simpler and cheaper prediction of INH PK. Further exploration of the impact of SLCO1B1 SNPs on RIF PK is required in this and other populations. Clinical Trials Registration. NCT01408914.
一线抗结核药物（利福平[RIF]、异烟肼[INH]和吡嗪酰胺[PZA]）的药代动力学（PK）变异性很高，可能受药物遗传多态性影响。我们在90名参与者中进行了一项药物遗传学亚研究，这些参与者有来自秘鲁HIRIF试验的PK数据。
使用实时聚合酶链反应（PCR）对NAT2、SLCO1B1、AADAC和AOX1基因座中的相关单核苷酸多态性（SNP）进行基因分型。
传统的6-SNP NAT2检测板预测的慢乙酰化、中间乙酰化和快乙酰化比例分别为32.5%、48.2%和19.2%。单个NAT2标签SNP（rs1495741）与检测板预测的表型符合率为91%，并且是INH曲线下面积（AUC）的更好预测指标。考虑到可能由检测板中未包含的罕见等位基因或可使用观察到的AUC明确解决的差异所导致的不一致，标签SNP的敏感性为97.7%。SLCO1B1中一个先前描述的SNP（rs4149032）的等位基因频率为0.31，尽管等位基因在随机分组中分布极端，但似乎在20mg/kg剂量下影响RIF的AUC和最大浓度（Cmax）。AADAC SNP（rs1803155）在研究人群中占主导地位，且与RIF的PK无关联，不过由于样本量和等位基因频率的原因，可能遗漏了其效应。AOX1中的一个常见SNP（rs55754655）与PZA的PK无关联。
标签SNP方法可能为INH的PK提供更简单、更经济的预测。需要在本研究人群及其他人群中进一步探索SLCO1B1 SNP对RIF PK的影响。临床试验注册。NCT01408914。
