Gepotidacin is a first-in-class triazaacenaphthylene antibacterial that inhibits bacterial type II topoisomerases and has in vitro activity against a range of bacterial pathogens, including Escherichia coli. Urinary tract infections often progress to pyelonephritis and are a worldwide problem due to the prevalence of multidrug-resistant E. coli strains. This study evaluated the in vivo efficacy of gepotidacin against four strains of multidrug-resistant E. coli in a rat pyelonephritis model. Infected rats received controlled intravenous infusions of gepotidacin every 12 h for 4 days that recreated human systemic exposures from oral gepotidacin (800 or 1,500 mg twice daily for 4 days). Liquid chromatography-tandem mass spectrometry analysis of blood samples and kidney homogenates showed that gepotidacin levels were 6- to 7-fold higher in kidneys than in blood. Across experiments with 4-day gepotidacin treatments, bacterial CFU in kidneys were reduced by 2.9 to 4.9 log10 compared to pretreatment levels, and bladder CFU were reduced to the lower limit of detection (1.2 log10). The efficacies of 800- and 1,500-mg gepotidacin exposures were statistically similar. A time-course experiment indicated that a period of more than 24 h of gepotidacin treatment was required for efficacy and that 4 days were needed for maximal response. Overall, these results demonstrate that the recreated human exposures of gepotidacin studied were effective in an animal model of pyelonephritis caused by multidrug-resistant E. coli and that further evaluation for clinical use is warranted.
Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action with an in vitro spectrum of activity that includes Escherichia coli . Our objectives herein were the following: 1) to identify the pharmacokinetic-pharmacodynamics (PK-PD) index associated with efficacy for gepotidacin against E. coli ; 2) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction endpoints for E. coli ; and 3) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-hour one-compartment in vitro infection model was used to investigate the first two study objectives and a 10-day hollow-fiber in vitro infection model was used to evaluate the third objective. For the dose-fractionation studies (objective 1), in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin area under the concentration-time curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as PK-PD index most closely associated with change in bacterial burden ( R 2 = 0.925). For the dose-ranging studies (objective 2), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/L) were studied, the magnitude of the median free-drug gepotidacin AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log 10 CFU reductions for the pooled dataset was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective 3), in which one isolate ( E. coli NCTC 13441 gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin AUC/MIC ratios 275 and greater were sufficient to suppress on-therapy resistance amplification. Together, the data generated from these studies will be useful to support discrimination among candidate dosing regimens for future clinical study.
Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions (P ≤ 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for S. pneumoniae and H. influenzae (mean log10 reductions, 1.6 to ≥2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against S. aureus (mean log10 reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against S. aureus with the 1,500-mg oral dose (mean log10 reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community-associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies.
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