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

Author

Hoover, Jennifer, Lewandowski, Thomas, Straub, Robert J., Novick, Steven J., DeMarsh, Peter, Aubart, Kelly, Rittenhouse, Stephen, and Zalacain, Magdalena

Abstract

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.

Published
2015
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3. Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.

Author

Hoover J, Lewandowski T, Straub RJ, Novick SJ, DeMarsh P, Aubart K, Rittenhouse S, and Zalacain M

Subjects
Amidohydrolases antagonists & inhibitors, Amidohydrolases metabolism, Animals, Anti-Bacterial Agents blood, Anti-Bacterial Agents pharmacology, Area Under Curve, Bacterial Proteins antagonists & inhibitors, Bacterial Proteins metabolism, Bridged Bicyclo Compounds, Heterocyclic blood, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Enzyme Inhibitors blood, Enzyme Inhibitors pharmacology, Haemophilus Infections blood, Haemophilus Infections microbiology, Haemophilus influenzae drug effects, Haemophilus influenzae enzymology, Haemophilus influenzae growth & development, Hydroxamic Acids blood, Hydroxamic Acids pharmacology, Lung drug effects, Lung microbiology, Male, Mice, Microbial Sensitivity Tests, Pneumonia, Pneumococcal blood, Pneumonia, Pneumococcal microbiology, Rats, Rats, Sprague-Dawley, Staphylococcal Infections blood, Staphylococcal Infections microbiology, Staphylococcus aureus drug effects, Staphylococcus aureus enzymology, Staphylococcus aureus growth & development, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae enzymology, Streptococcus pneumoniae growth & development, Anti-Bacterial Agents pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Enzyme Inhibitors pharmacokinetics, Haemophilus Infections drug therapy, Hydroxamic Acids pharmacokinetics, Pneumonia, Pneumococcal drug therapy, Staphylococcal Infections drug therapy
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. pneumoniae, 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 (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 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, fAUC correlated better with efficacy than fAUC/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 fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Published
2015
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