Contribution of genetic variation to pharmacokinetic variability and toxicity in

遗传变异对药代动力学变异和毒性的影响

• 批准号: 8530171
• 负责人: Dissou Affolabi
• 金额: $ 0.5万
• 依托单位: NAT'L HOSPITAL/TUBERCULOSIS/PUL/DISEASES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530171
• 关键词: Africa; Africa South of the Sahara; African; Age; Antitubercular Agents; Biological; Cells; Cessation of life; Characteristics; Collaborations; Complex; Country; Development; Disease; Drug Exposure; Drug Kinetics; Drug Targeting; Enrollment; Enzymes; Ethambutol; Ethnic Origin; Gatifloxacin; Genes; Genetic; Genetic Variation; Guinea; HIV; HIV Seropositivity; Heterogeneity; Hospitals; Hygiene; In Vitro; Individual; Individual Differences; Interruption; London; Medical Research; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Psychological Transfer; Psychological reinforcement; Pulmonary Tuberculosis; Pyrazinamide; RNA Interference; Randomized; Randomized Controlled Trials; Reaction; Reporting; Research; Rifampin; Role; Safety; Sampling; Schools; Senegal; Site; South Africa; System; Technology Transfer; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tropical Medicine; Tuberculosis; Universities; drug metabolism; experience; genetic analysis; genome-wide; isoniazid; pathogen; programs; response; screening; sex; treatment adherence; treatment trial; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): In 2010 there were an estimated 8.8 million incident cases of tuberculosis (TB) globally, with 2.3 million of these reported in Africa, 1.1 million deats among HIV-negative cases of TB and an additional 0.35 million deaths among people who were HIV-positive. The complex relationship between TB pathogen, host, and drug exposure in the pathogenesis of TB is poorly understood. The treatment regimen that is currently recommended by WHO for new cases of drug-susceptible TB is highly efficacious, with cure rates of around 90% in HIV-negative patients. However, even if all new TB cases were treated and patients were adherent to the treatment, there would still be 10% of patients (i.e. 880,000 patients worldwide, 230,000 patients in Africa) who fail to respond to treatment. Even if adherent to treatment, a proportion of patients, with rifampicin sensitive TB, are slow to respond to medication or are non-responders. The problem is even more complex and serious in HIV infected patients where the efficacy of the current treatments appears to be lower. Still other patients can be treated successfully, but will experience toxicity and thus treatment interruptions. While several potential determinants of the variable response to drug treatment are recognized (e.g. sex, age, ethnicity), much of the variability in response to anti-tuberculosis drugs remains unexplained. In recent years there has been a rapid development in the understanding of the genetics underlying inter- individual differences in drug metabolism and treatment efficacy. The field of pharmacogenetics encompasses the study of the heterogeneity in genes related to drug transporters, drug metabolizing enzymes and drug targets, in the context of efficacy of treatment and adverse drug reactions. Few studies have been conducted to explore this field for TB disease. Through this study we aim to explore and determine host genetic factors contributing to pharmacokinetic (i.e. drug concentration) and dynamic (i.e. treatment outcome) variability in TB patients. The "RAFAgene" study is a 4 year project which will be nested within two multi-country randomized phase III tuberculosis treatment trials, the OFLOTUB and RAFA trials (reg numbers NCT00216385 and PACTR 201105000291300) conducted in Sub-Saharan Africa. Patients enrolled in the pharmacokinetic studies within these 2 trials will be sampled for genetic analysis (genome-wide and targeted SNPs screening with in vitro confirmation of the biological plausibility of the association between pharmacokinetic and genetic characteristics). The proposed project is led by Dr. Dissou Affolabi at the National Hospital for TB and Pulmonary (NHTPD) with partners from the National TB program in Senegal, the University Ignace Deen in Guinea, the University of Cape Town (SA), the Medical Research Council in Durban (South Africa), the University of Liverpool UK and the London School of Hygiene and Tropical Medicine UK.

描述（由申请人提供）：2010年，全球估计有880万例结核病（TB）病例，其中230万例在非洲报告，110万例HIV阴性结核病病例死亡，另有35万例HIV阳性患者死亡。结核病发病机制中结核病病原体、宿主和药物暴露之间的复杂关系知之甚少。世卫组织目前推荐的对药物敏感的结核病新发病例的治疗方案非常有效，艾滋病毒阴性患者的治愈率约为90%。然而，即使所有新发结核病病例都得到治疗，患者也坚持接受治疗，仍有10%的患者（即全球88万患者，非洲23万患者）对治疗无效。即使坚持治疗，也有一部分利福平敏感性结核病患者对药物反应缓慢或无反应。 在HIV感染患者中，这个问题甚至更加复杂和严重，目前的治疗效果似乎较低。还有一些患者可以成功治疗，但会出现毒性，从而中断治疗。虽然认识到对药物治疗的可变反应的几个潜在决定因素（例如性别、年龄、种族），但抗结核治疗反应的大部分可变性 毒品仍然无法解释。近年来，对药物代谢和治疗效果个体间差异的遗传学基础的理解有了快速发展。药物遗传学领域包括在治疗效果和药物不良反应的背景下，研究与药物转运蛋白、药物代谢酶和药物靶点相关的基因的异质性。很少有研究探索结核病的这一领域。通过这项研究，我们的目的是探索和确定宿主遗传因素，有助于药代动力学（即药物浓度）和动态（即治疗结果）的变化，在结核病患者。“RAFAgene”研究是一项为期4年的项目，将嵌套在两项多国随机III期结核病治疗试验中，即在撒哈拉以南非洲进行的OFLOTUB和RAFA试验（注册号NCT 00216385和PACTR 201105000291300）。将对入组这2项试验的药代动力学研究的患者进行采样，以进行遗传分析（全基因组和靶向SNP筛查，并在体外确认药代动力学和遗传特征之间相关性的生物学可接受性）。拟议项目由国家结核病和肺病医院（NHTPD）的Dissou Affolabi博士领导，合作伙伴来自塞内加尔国家结核病计划、几内亚伊尼亚斯迪恩大学、南非开普敦大学、南非德班医学研究理事会、英国利物浦大学和英国伦敦卫生和热带医学院。