PHARMACOKINETIC ISSUES IN THE USE OF MOXIFLOXACIN FOR TREATMENT OF TUBERCULOSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本研究的主要目的是比较健康志愿者单独使用莫西沙星与莫西沙星联合利福平的药代动力学，比较莫西沙星在接受多药治疗（异烟肼、利福平和吡嗪酰胺）的结核病患者中与接受莫西沙星加利福平的健康志愿者中的药代动力学。次要目的是：确定莫西沙星药代动力学在肺结核患者中在异烟肼、利福平和吡嗪酰胺强化期方案中的受试者间变化；比较莫西沙星与乙胺丁醇联合治疗活动性肺结核（异烟肼、利福平、吡嗪酰胺、莫西沙星或乙胺丁醇联合治疗方案）患者的血清异烟肼和利福平浓度；确定MDR1基因型（p -糖蛋白）多态性与利福平药代动力学参数之间的关系；研究MDR1基因型多态性对莫西沙星药代动力学的影响；确定MDR1基因型多态性对n -乙酰转移酶基因型（NAT2）调整的异烟肼药动学参数的影响；通过多变量回归分析确定莫西沙星或利福平药代动力学参数与结核病严重程度标志物之间的关系，包括两个月培养阳性、空洞性肺病、体重指数、体重、PK前研究治疗持续时间、合共病和c反应蛋白等协变量。研究计划：本研究将招募两组患者：(a)健康志愿者和(b)正在接受莫西沙星/利福平方案治疗的结核病患者，他们是TBTC研究27或其他TBTC临床试验的参与者。基于以往研究中的莫西沙星药代动力学（PK）参数（Tmax为- 1-3小时，血浆半衰期为12.1±3.1小时），服药后0、0.5、1.0、1.5、2、3、4、6、8、12、16和24小时的抽样方案应能准确估计最大浓度和AUC。方法：在药代动力学亚研究中，将莫西沙星单独在健康志愿者体内的药代动力学与莫西沙星联合利福平在健康志愿者体内的药代动力学进行比较。莫西沙星在接受多种药物治疗（异烟肼、利福平和吡嗪酰胺）的结核病患者中的药代动力学将与莫西沙星与利福平在健康志愿者中的药代动力学进行比较。临床相关性：TBTC最近的药代动力学研究表明，活动性肺结核患者的异烟肼、利福平、利福布汀和利福喷丁的血清浓度略低于健康志愿者。一般来说，氟喹诺酮类抗生素吸收良好，即使在活动性感染患者中也是如此。然而，这些研究并未对活动性肺结核患者进行专门评估。

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.