PHARMACOKINETIC ISSUES IN THE USE OF MOXIFLOXACIN FOR TREATMENT OF TUBERCULOSIS

使用莫西沙星治疗结核病的药代动力学问题

• 批准号: 7718709
• 负责人: MARC H WEINER
• 金额: $ 0.07万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718709
• 关键词: ABCB1 gene; Antibiotics; Body mass index; C-reactive protein; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Drug Kinetics; Enrollment; Ethambutol; Fluoroquinolones; Funding; Genetic Polymorphism; Genotype; Grant; Half-Life; Hour; Infection; Ingestion; Institution; Lung diseases; Morbidity - disease rate; Moxifloxacin; NAT2 gene; P-Glycoprotein; P-Glycoproteins; Participant; Patients; Persons; Pharmaceutical Preparations; Phase; Plasma; Pulmonary Tuberculosis; Pyrazinamide; Regression Analysis; Research; Research Personnel; Resources; Rifabutin; Rifampin; Sampling; Scheme; Serum; Severity of illness; Source; Treatment Protocols; Tuberculosis; United States National Institutes of Health; Variant; Weight; base; clinically relevant; healthy volunteer; human NAT2 protein; isoniazid; rifapentine; tuberculosis treatment

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objectives of this study are to compare in healthy volunteers the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin and to compare the pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid, rifampin, and pyrazinamide) to those of healthy volunteers receiving moxifloxacin plus rifampin. Secondary objectives are: to determine the inter-subject variation of moxifloxacin pharmacokinetics among patients with pulmonary tuberculosis while on an intensive-phase regimen with isoniazid, rifampin and pyrazinamide; to compare serum concentrations of isoniazid and rifampin among patients being treated with moxifloxacin versus patients being treated with ethambutol as the fourth drug in multidrug treatment of active tuberculosis (regimen of isoniazid, rifampin, pyrazinamide and moxifloxacin or ethambutol); to determine the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin pharmacokinetic parameters; to determine the effect of polymorphisms of MDR1 genotype on moxifloxacin pharmacokinetics; to determine the effect of polymorphisms of MDR1 genotype on isoniazid pharmacokinetic parameters adjusted for N-acetyltransferase genotype (NAT2); to determine by multivariate regression analyses the associations between moxifloxacin or rifampin pharmacokinetic parameters and markers of tuberculosis disease severity including the covariates of two-month culture positivity, cavitary lung disease, Body Mass Index, weight, duration of study treatment prior to PK, co-morbidities and C-reactive protein. RESEARCH PLAN: This study will enroll two groups of patients: (a) healthy volunteers and (b) patients being treated for tuberculosis with a moxifloxacin/rifampin regimen who are participants in TBTC Study 27 or another TBTC clinical trial. Based on moxifloxacin pharmacokinetic (PK) parameters in pervious studies (Tmax - 1-3 hours and plasma half-life of 12.1 plus or minus 3.1 hours), a sampling scheme of 0, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post drug ingestion should provide accurate estimates of maximum concentration and AUC. METHODS: In the pharmacokinetic sub-study, the pharmacokinetics of moxifloxacin alone in healthy volunteers will be compared to the pharmacokinetics of moxifloxacin administered with rifampin in healthy volunteers. The pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid, rifampin, and pyrazinamide) will be compared to the pharmacokinetics of moxifloxacin administered with rifampin in healthy volunteers. CLINICAL RELEVANCE: Recent pharmacokinetic studies by the TBTC suggest that patients with active tuberculosis have somewhat lower serum concentrations of isoniazid, rifampin, rifabutin, and rifapentine than were seen in studies of healthy volunteers. In general, the fluoroquinolone antibiotics are well absorbed, even among persons with active infections. However, patients with active tuberculosis have not been specifically evaluated in these studies.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：这项研究的主要目标是在健康志愿者中比较单独使用的莫西沙星的药代动力学与用rifampin施用的莫西沙星的药代动力学，并比较莫西弗洛沙星的药代动力学，比较了多种药物治疗的患者的莫西弗洛沙星的药代动力学（与健康的摩西蛋白酶治疗（Isoniaiaiaiaiaiaiazid），以及rifampIns，rifampins，rifampins，rifampins in接受莫西沙星和利福平。 次要目标是：确定肺结核患者莫西法沙星药代动力学的受试者间变化，而在具有异念珠菌，利福平和吡嗪酰胺的强化相期方案上；比较接受莫西沙星治疗的异念珠菌和利福平的血清浓度与用乙酰丁醇治疗的患者在多药治疗活性结核病的多种治疗（异索尼亚二氮二，利福平，吡唑胺和莫克沙酰胺和莫昔霉素或埃替醇）中。确定MDR1基因型（P-糖蛋白）和利福平药代动力学参数的多态性之间的关联；确定MDR1基因型多态性对莫西法沙星药代动力学的影响；确定MDR1基因型多态性对针对N-乙酰基转移酶基因型（NAT2）调整的异念珠菌药代动力学参数的影响；通过多元回归确定，分析了莫西弗洛沙星或利福平药代动力学参数和结核病疾病严重程度的标志物，包括两个月培养阳性，腔肺疾病，体重指数，体重指数，PK之前的研究治疗持续时间，共co和c-co-Morbiditive and C-Rective fortive。 研究计划：这项研究将招募两组患者：（a）健康志愿者和（b）接受TBTC研究的参与者27或另一项TBTC临床试验的莫西法沙星/利福平治疗患者。 基于透明研究中的Moxifloxacin药代动力学（PK）参数（TMAX-1-3小时，血浆半衰期为12.1 plus或减去3.1小时），0、0.5、1.0、1.5、1.5、1.5、2、2、2、2、3、4、6、6、8、12、16、16、16、16、16、16、16、16、16、16、16、12、16和24小时应提供的浓度的精确估计和AUC的浓度最高。 方法：在药代动力学的子研究中，仅在健康志愿者中，单独的莫西法沙星的药代动力学与健康志愿者施用的莫西法沙星的药代动力学进行比较。 结核病患者中莫西法沙星的药代动力学将与多药治疗（异烟肼，利福平和吡嗪酰胺）进行比较，将其与健康的志愿者在健康的志愿者中用Rifampin施用的Moxifloxacin的药代动力学。 临床相关性：TBTC的最新药代动力学研究表明，与健康志愿者的研究相比，血清中的活性结核病患者的血清浓度低一些。 通常，即使在具有活性感染的人中，氟喹诺酮抗生素也被充分吸收。 但是，在这些研究中尚未对患有活性结核病的患者进行特殊评估。