Pharmacokinetic and pharmacodynamic evaluation of AZD5847 in a mouse model of tuberculosis

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.