Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis |
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| Authors: | Jayaram Ramesh Gaonkar Sheshagiri Kaur Parvinder Suresh B L Mahesh B N Jayashree R Nandi Vrinda Bharat Sowmya Shandil R K Kantharaj E Balasubramanian V |
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| Affiliation: | AstraZeneca India Pvt Ltd, Malleswaram, Bangalore 560003, India. |
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| Abstract: | 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 (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation. |
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