This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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
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.
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