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

ABSTRACTGSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitroactivity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivopharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniaeand 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 vivoefficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniaeand S. aureusisolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae(R2, 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus(R2, 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniaeisolates (R2, 0.62) and 7.2 and 13.0 for five H. influenzaeisolates (R2, 0.93). The data showed that for eight S. aureusisolates, fAUC correlated better with efficacy than fAUC/MIC (R2, 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 fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10reductions, respectively, for S. aureus.