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

项目摘要 发现有效的抗生素治疗和结核病的化学预防， 历史上最具影响力的科学和公共卫生进步之一。但据 越来越清楚的是，向所有人提供相同的剂量会导致高度可变的 药物浓度，导致过度的毒性风险和不良的治疗结果。 对于异烟肼，最广泛使用的结核病治疗和预防药物 治疗中，由于共同的代谢，存在高度的个体间差异。 NAT 2基因的多态性有两个NAT 2拷贝突变的个体 赋予降低的活性（“慢乙酰化剂”）的药物毒性风险增加， 而没有降低活性突变的个体（“快速乙酰化者”）， 增加治疗失败、复发和获得性耐药性的风险。主要障碍 实施药物基因组学指导的给药来解决这些问题， 缺乏诊断方法，也缺乏关于如何根据 乙酰化基因型我们最近开发了一种基于生物芯片的快速分子 关键NAT 2多态性的诊断和准确预测 乙酰化基因型我们建议：1）在不同人群中验证该测定法， 巴西使用非侵入性样本，包括手指针刺血和口腔拭子;以及2） 进行I期临床试验，以确定药物基因组学指导剂量 每周接受异烟肼和利福喷丁预防的人群中的变化 治疗可以减少药物水平的变化。总的来说，该项目将产生 结核病个性化治疗的基础数据， 预防性治疗，以减少不良事件并改善这种疾病的结局， 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.