Point-of-care pharmacogenomic testing to optimize isoniazid dosing for tuberculosis prevention

项目概要 发现了有效的抗生素治疗和化学预防结核病的方法 历史上最具影响力的科学和公共卫生进步之一。然而，它是 越来越清楚的是，向所有个体提供相同的剂量会导致高度可变的结果 药物浓度，导致毒性风险过高和治疗结果不佳。 异烟肼是治疗和预防结核病最广泛使用的药物 治疗中，由于常见的原因，新陈代谢存在高度的个体差异。 NAT2 基因的多态性。拥有两个带有突变的 NAT2 拷贝的个体 导致活性降低（“慢乙酰化剂”）的药物毒性风险增加， 而没有突变降低活性的个体（“快速乙酰化物”），则处于 治疗失败、复发和获得性耐药的风险增加。主要障碍 实施药物基因组学指导的剂量来解决这些问题已经 缺乏诊断，也缺乏如何根据不同情况调整异烟肼剂量的数据 乙酰化基因型。我们最近开发了一种基于墨盒的快速分子 关键 NAT2 多态性的诊断和准确预测的算法 乙酰化基因型。我们建议：1）在不同人群中验证该测定 巴西使用非侵入性样本，包括指尖采血和口腔拭子；和 2) 进行 I 期临床试验以确定药物基因组学指导剂量是否 对每周接受异烟肼和利福喷丁预防性治疗的人群进行修改 治疗可以减少药物水平的变化。总体而言，该项目将产生 走向个性化结核病治疗的基础数据 预防性治疗，以减少不良事件并改善这种疾病的结果 全球重要性。

Project Summary The discovery of effective antibiotic treatment and chemoprevention for tuberculosis was among the most impactful scientific and public health advances in history. However, it is increasingly clear that providing the same doses to all individuals leads to highly variable drug concentrations, resulting in excess risk of toxicities and poor treatment outcomes. For isoniazid, the most widely used drug for tuberculosis treatment and preventive therapy, there is a high degree of interindividual variation in metabolism due to common polymorphisms in the NAT2 gene. Individuals who have two NAT2 copies with mutations conferring reduced activity (“slow acetylators”) are at increased risk of drug toxicities, while individuals without mutations reducing activity (“rapid acetylators”), are at increased risk of treatment failure, relapse, and acquired drug resistance. Major barriers to implementing pharmacogenomic-guided dosing to address these problems have been the lack of a diagnostic and lack of data on how to adjust isoniazid doses according to acetylator genotype. We recently developed a cartridge-based, rapid molecular diagnostic for the key NAT2 polymorphisms and an algorithm that accurately predicts acetylator genotype. We propose to: 1) validate this assay in a diverse population in Brazil using non-invasive samples, including fingerstick blood and oral swabs; and 2) perform a Phase I clinical trial to determine whether pharmacogenomic-guided dose modification among people receiving weekly isoniazid and rifapentine for preventive therapy can reduce variation in drug levels. Overall, this project will generate foundational data in the move towards personalizing tuberculosis treatment and preventive therapy to reduce adverse events and improve outcomes for this disease of global importance.