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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

Ramesh Jayaram, Sheshagiri Gaonkar, Parvinder Kaur, B. L. Suresh, B. N. Mahesh, R. Jayashree, Vrinda Nandi, Sowmya Bharat, R. K. Shandil, E. Kantharaj, and V. Balasubramanian*

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.

* Corresponding author. Mailing address: AstraZeneca India Pvt. Ltd., 277, T. Chowdaiah Rd., Malleswaram, Bangalore 560003, India. Phone: 91-80-3340372, ext. 296. Fax: 91-80-3340449. E-mail: bala.subramanian{at}astrazeneca.com.

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.



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