Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection

Abstract

ABSTRACT GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumonia e, H. influenzae , and S. aureus . Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC ( f AUC/MIC) index in S. pneumoniae ( R 2 , 0.83), whereas f AUC/MIC and free maximum drug concentration ( fC max )/MIC were the best efficacy predictors for S. aureus ( R 2 , 0.9 and 0.91, respectively). Median daily f AUC/MIC values required for stasis and for a 1-log 10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates ( R 2 , 0.62) and 7.2 and 13.0 for five H. influenzae isolates ( R 2 , 0.93). The data showed that for eight S. aureus isolates, f AUC correlated better with efficacy than f AUC/MIC ( R 2 , 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). Median f AUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log 10 reductions, respectively, for S. aureus .