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

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.

• 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 7 Pg. 4185-90 (Jul 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24820085 (Publication Type: Journal Article)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Oxazolidinones
• posizolid

Topics

• Animals
• Area Under Curve
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Dosage Calculations
• Drug Resistance, Multiple, Bacterial
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects)
• Oxazolidinones (pharmacokinetics, therapeutic use)
• Tuberculosis, Pulmonary (drug therapy, microbiology)