title: 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.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: V
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India suresh.solapure@astrazeneca.com.
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: K N
authors.initials: KN
authors.lastname: Mahesh
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Jitender
authors.initials: J
authors.lastname: Reddy
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.affiliation: AstraZeneca India Pvt. Ltd., Hebbal, Bangalore, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Kumar
authors.affiliation: AstraZeneca UK, Mereside, Alderly Park, Macclesfield, Cheshire, England.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Wright
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA.
authors.forename: David
authors.initials: D
authors.lastname: Melnick
authors.affiliation: AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Butler
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D024901:Drug Resistance, Multiple, Bacterial; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D023303:Oxazolidinones; C453362:posizolid