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

  • Antimicrob Agents Chemother. 2014 Jul;58(7):4185-90. doi: 10.1128/AAC.00137-14.
V Balasubramanian  1 ,  Suresh Solapure  2 ,  Radha Shandil  1 ,  Sheshagiri Gaonkar  1 ,  K N Mahesh  1 ,  Jitender Reddy  1 ,  Abhijeet Deshpande  1 ,  Sowmya Bharath  1 ,  Naveen Kumar  1 ,  Lindsay Wright  3 ,  David Melnick  4 ,  Scott L Butler  5
Affiliations
  • 1. AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
  • 2. AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India [email protected].
  • 3. AstraZeneca UK, Mereside, Alderly Park, Macclesfield, Cheshire, England.
  • 4. AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.
  • 5. AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
PMID: 24820085 DOI: 10.1128/AAC.00137-14
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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