PHARMACOKINETIC ISSUES IN THE USE OF MOXIFLOXACIN FOR TREATMENT OF TUBERCULOSIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：本研究的主要目的是在健康志愿者中比较单用利福沙星与利福沙星联合给药的药代动力学，并比较利福沙星在接受多药治疗（异烟肼、利福平和吡嗪酰胺）的结核病患者与接受利福沙星联合利福平治疗的健康志愿者中的药代动力学。 次要目的是：确定接受异烟肼、利福平和吡嗪酰胺强化治疗方案的肺结核患者中利福沙星药代动力学的受试者间差异;比较活动性结核病多药联合治疗中，以沙丁胺醇作为第四种药物治疗的患者与以沙丁胺醇作为第四种药物治疗的患者的血清异烟肼和利福平浓度（异烟肼、利福平、吡嗪酰胺和莫西沙星或乙胺丁醇的治疗方案）;确定MDR 1基因型多态性之间的关联探讨MDR 1基因多态性对利福沙星药动学的影响;确定MDR 1基因型多态性对N-乙酰转移酶基因型（NAT 2）校正后异烟肼药代动力学参数的影响;通过多变量回归分析确定利福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联，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、合并症和C反应蛋白。 研究报告：本研究将入组两组患者：（a）健康志愿者和（B）正在接受利多卡因/利福平方案治疗结核病的患者，他们是TBTC研究27或另一项TBTC临床试验的参与者。 基于既往研究中的利福沙星药代动力学（PK）参数（Tmax - 1-3小时，血浆半衰期为12.1 ± 3.1小时），药物摄入后0、0.5、1.0、1.5、2、3、4、6、8、12、16和24小时的采样方案应提供最大浓度和AUC的准确估计值。 方法：在药代动力学子研究中，将比较健康志愿者中单用利福沙星的药代动力学与健康志愿者中利福沙星与利福平联合给药的药代动力学。 将在接受多药治疗（异烟肼、利福平和吡嗪酰胺）的结核病患者中比较利福沙星的药代动力学，并在健康志愿者中比较利福沙星与利福平联合给药的药代动力学。 临床相关性：TBTC最近的药代动力学研究表明，活动性结核病患者的异烟肼、利福平、利福朋和利福喷丁血清浓度略低于健康志愿者研究中的浓度。 一般来说，氟喹诺酮类抗生素吸收良好，即使在活动性感染的人群中也是如此。 然而，这些研究中尚未对活动性结核病患者进行专门评估。

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.