Efficacy of Human Exposures of Gepotidacin (GSK2140944) against Escherichia coli in a Rat Pyelonephritis Model

Abstract

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.

Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis)

“…The microbiological activity of gepotidacin includes E. coli, the key causative uropathogen of uUTI, and S. saprophyticus and Enterococcus faecalis. In addition, the efficacy of gepotidacin against E. coli was evaluated in a rat pyelonephritis model, which indicated potential efficacy in uUTI and supported clinical dose selection (19). The pharmacokinetics (PK) of gepotidacin have been well defined in healthy participants and demonstrated urine exposures that may support uUTI treatment (20)(21)(22)(23).…”

Antibacterial Activity of the Novel Drug Gepotidacin against Stenotrophomonas maltophilia—An In Vitro and In Vivo Study

“…Gepotidacin showed no toxicity in G. mellonella. The tested concentration was previously safely examined in a rat pyelonephritis model [ 26 ]. Furthermore, Barth et al assessed the safety and systemic exposure of gepotidacin in healthy adults as well as in adolescents.…”

Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections

“…Although cystitis models are the predominant animal model for studying uUTIs ( 22 ), uUTI and cystitis models in rodents can be variable and highly strain dependent, with marked self-resolution in untreated animals ( 23 , 24 ). As such, a rat pyelonephritis (more indicative of cUTI) model was selected for the initial evaluation of the in vivo efficacy of GEP against E. coli ( 25 ). Although pyelonephritis is a more severe infection than cystitis, the model was chosen based on its robustness and reproducibility ( 25 ), and interpreting the results from this model in the context of uUTI can be considered conservative.…”