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

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 dosedependent 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 (fC max )/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-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, 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 g/ml). Median fAUCs of 2.1 and 6.3 g · h/ml were associated with stasis and 1-log 10 reductions, respectively, for S. aureus.

Generating Robust and Informative Nonclinical In Vitro and In Vivo Bacterial Infection Model Efficacy Data To Support Translation to Humans

“…Collecting serial blood samples from the same animal (e.g., multiple retro-orbital, facial vein, or tail vein bleeds) at different time points better informs the PK parameters and allows one to separate animal variability from residual error noise (e.g., bioanalytical noise). Serial blood sampling may not be possible in all infection models; however, methods have been developed and employed by some investigators (109–116). Destructive sampling with one PK sample per mouse remains the most common approach.…”

Port d’Entrée for Respiratory Infections – Does the Influenza A Virus Pave the Way for Bacteria?

“…In bacteriological studies rats are more frequently used. There are numerous rat models investigating the impact of diabetes ( Oliveira et al, 2016 ), metabolic syndromes ( Feng et al, 2015 ), cirrhosis ( Preheim et al, 1991 ), pharmaco-kinetics and dynamics ( Antonopoulou et al, 2015 ; Hoover et al, 2015 ), intoxication ( Davis et al, 1991 ), immunization ( Iinuma and Okinaga, 1989 ), and general bacterial virulence factors ( Shanley et al, 1996 ) on development of pneumococcal, streptococcal, and staphylococcal pneumonia and lung pathology. Unfortunately, there are only few studies on bacterial and viral co-infections in rats.…”

Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats

“…The exposure profiles measured in the rats closely matched those reported in humans, with both similar AUC and similar C max values being achieved. PK/PD studies have demonstrated that the AUC correlates with efficacy for GSK1322322 and that the AUCs achieved with these recreated human profiles predict efficacy against S. pneumoniae , H. influenzae , and S. aureus ( 12 ). In fact, the efficacy of the 1,500-mg q12h dosing regimen against skin infections was clinically confirmed in a multicenter, randomized phase IIa trial ( 13 ), thus highlighting the ability of this preclinical model to predict efficacy in patients.…”

“…The human exposure profiles recreated in rats were not adjusted for relative differences in protein binding between rat and human since the protein binding values for GSK1322322 and all comparator compounds are similar between the species ( 9 , 12 , 18 – 22 ). Similarly, the recreated profiles were based on systemic drug levels and do not account for differences in rat and human lung uptake.…”