2014•Antimicrobial Agents and ChemotherapyOpen access
Pharmacokinetic and Pharmacodynamic Evaluation of AZD5847 in a Mouse Model of Tuberculosis
Venkataraman Balasubramanian, Suresh M. Solapure, Radha Krishan Shandil, Sheshagiri Gaonkar, Krishna Mahesh, Jitender Reddy, Abhijeet Yashwantrao Deshpande, Sowmya Bharath, Naveen Kumar, Lindsay Wright, David Melnick, Scott L. Butler
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Abstract
AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration of AZD5847 to mice infected with M. tuberculosis H37Rv in a chronic-infection model resulted in a 1.0-log10 reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥ 20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater.