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

项目摘要 发现了结核病的有效抗生素治疗和化学预防 这是历史上影响最大的科学和公共卫生进步之一。然而，它是 越来越清楚的是，向所有人提供相同的剂量会导致高度不同的 药物浓度过高，导致中毒风险过高，治疗结果不佳。 对于异烟肼，最广泛使用的结核病治疗和预防药物 治疗上，新陈代谢有高度的个体间差异，这是由于共同的 NAT2基因的多态性。具有两个带有突变的Nat2拷贝的个人 活性降低(“慢乙酰化”)的药物中毒风险增加， 而没有突变降低活性的个体(“快速乙酰化者”)则处于 增加治疗失败、复发和获得性耐药性的风险。主要障碍 为了实施药物基因组指导给药来解决这些问题 缺乏诊断和关于如何调整异烟肼剂量的数据 乙酰化基因。我们最近开发了一种基于卡盒的快速分子 对关键的NAT2基因多态性进行诊断，并使用算法准确预测 乙酰化基因。我们建议：1)在不同的人群中验证这一检测方法 巴西使用非侵入性样本，包括指纹血样和口腔拭子；和2) 进行I期临床试验，以确定药物基因组指导剂量 每周接受异烟肼和利福喷丁预防的人群中的改进 治疗可以减少药物水平的变化。总体而言，该项目将产生 结核病个人化治疗的基础数据和 预防性治疗以减少不良事件并改善这种疾病的预后 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.