Pharmacokinetic and Pharmacodynamic Evaluation of AZD5847 in a Mouse Model of Tuberculosis |
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| Authors: | V Balasubramanian Suresh Solapure Radha Shandil Sheshagiri Gaonkar K N Mahesh Jitender Reddy Abhijeet Deshpande Sowmya Bharath Naveen Kumar Lindsay Wright David Melnick Scott L Butler |
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| Institution: | aAstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India;bAstraZeneca UK, Mereside, Alderly Park, Macclesfield, Cheshire, England;cAstraZeneca Pharmaceuticals, Wilmington, Delaware, USA;dAstraZeneca R&D Boston, Waltham, Massachusetts, USA |
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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. |
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