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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：本研究的主要目的是比较莫西沙星和莫西沙星联合利福平在健康志愿者中的药代动力学，并比较接受异烟肼、利福平和吡津胺等多种药物治疗的结核病患者与莫西沙星联合利福平治疗的健康志愿者中莫西沙星的药代动力学。第二个目标是：确定异烟肼、利福平和吡嗪酰胺强化方案下肺结核患者莫西沙星药代动力学的对象间差异；比较接受莫西沙星和乙胺丁醇作为活动性肺结核多药治疗方案(异烟肼、利福平、吡津酰胺和莫西沙星或乙胺丁醇方案)的患者中异烟肼和利福平的血药浓度；确定mdr1基因(P-糖蛋白)多态性与利福平药代动力学参数之间的关系；确定mdr1基因多态性对莫西沙星药代动力学的影响；确定mdr1基因多态性对N-乙酰基转移酶(NAT2)药物动力学参数调整的影响；通过多元回归分析来确定莫西沙星或利福平的药代动力学参数与结核病严重程度标志的关系，包括两个月培养阳性、空洞肺疾病、体重指数、体重、PK前研究治疗时间、合并症和C反应蛋白等协变量。 研究计划：这项研究将招募两组患者：(A)健康志愿者和(B)接受莫西沙星/利福平方案治疗的结核病患者，他们是TBTC研究第27项或另一项TBTC临床试验的参与者。根据以往研究中的莫西沙星药代动力学(PK)参数(Tmax-1-3小时，血浆半衰期为12.1正负3.1小时)，服药后0、0.5、1.0、1.5、2、3、4、6、8、12、16和24小时的采样方案应能提供对最大浓度和AUC的准确估计。 方法：在药动学亚研究中，将莫西沙星在健康志愿者体内的药代动力学与莫西沙星与利福平合用后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(异烟肼、利福平和吡津胺)治疗的结核病患者中的药代动力学将与莫西沙星与利福平合用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比健康志愿者的研究中看到的要低一些。一般来说，氟喹诺酮类抗生素被很好地吸收，即使在活动性感染的人中也是如此。然而，这些研究没有对活动性肺结核患者进行具体评估。

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.