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Antimicrobial Agents and Chemotherapy, July 2003, p. 2118-2124, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2118-2124.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis

AstraZeneca India Pvt. Ltd., Malleswaram, Bangalore 560003, India

Received 12 July 2002/ Returned for modification 27 January 2003/ Accepted 26 March 2003

Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r² = 0.95), whereas the maximum concentration in serum/MIC (r² = 0.86) and the time that the concentration remained above the MIC (r² = 0.44) showed lesser degrees of correlation.

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