Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.
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.
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA Jennifer.L.Hoover@gsk.com.
Jennifer
J
Hoover
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Thomas
T
Lewandowski
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Robert J
RJ
Straub
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Steven J
SJ
Novick
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Peter
P
DeMarsh
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Kelly
K
Aubart
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Stephen
S
Rittenhouse
Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Magdalena
M
Zalacain
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006192:Haemophilus Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D006877:Hydroxamic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C583947:GSK1322322; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C084507:peptide deformylase