Pharmacokinetic-Pharmacodynamic Evaluation of Gepotidacin against Gram-Positive Organisms Using Data from Murine Infection Models

Abstract

Gepotidacin (formerly called GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae Using neutropenic murine thigh and lung infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Candidate models were fit to single-dose PK data from uninfected mice (for doses of 16 to 128 mg/kg of body weight given subcutaneously [s.c.]). Dose fractionation studies (1 isolate/organism; 2 to 512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2 to 2,048 mg/kg/day; MIC ranges of 0.5 to 2 mg/liter for S. aureus and 0.125 to 1 mg/liter for S. pneumoniae) were conducted. The presence of an in vivo postantibiotic effect (PAE) was also evaluated. Relationships between the change from baseline in log₁₀ CFU at 24 h and the ratio of the free-drug plasma area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio), the ratio of the maximum concentration of drug in plasma (C_max) to the MIC (C_max/MIC ratio), and the percentage of a 24-h period that the drug concentration exceeded the MIC (%T>MIC) were evaluated using Hill-type models. Plasma and epithelial lining fluid (ELF) PK data were best fit by a four-compartment model with linear distributional clearances, a capacity-limited clearance, and a first-order absorption rate. The ELF penetration ratio in uninfected mice was 0.65. Since the growth of both organisms was poor in the murine lung infection model, lung efficacy data were not reported. As determined using the murine thigh infection model, the free-drug plasma AUC/MIC ratio was the PK-PD index most closely associated with efficacy (r² = 0.936 and 0.897 for S. aureus and S. pneumoniae, respectively). Median free-drug plasma AUC/MIC ratios of 13.4 and 58.9 for S. aureus, and 7.86 and 16.9 for S. pneumoniae, were associated with net bacterial stasis and a 1-log₁₀ CFU reduction from baseline, respectively. Dose-independent PAE durations of 3.07 to 12.5 h and 5.25 to 8.46 h were demonstrated for S. aureus and S. pneumoniae, respectively.

Keywords: Staphylococcus aureus; Streptococcus pneumoniae; gepotidacin.

FIG 1

Relationships between change from baseline in log₁₀ CFU and gepotidacin free-drug plasma AUC/MIC ratio, C_max/MIC ratio, and %T>MIC for S. aureus 33591 (A) and S. pneumoniae 10183 (B), excluding the q24h dosing regimens. Symbols represent changes from baseline in log₁₀ CFU per thigh for individual mice at 24 h. The horizontal lines represent no net change from baseline.

FIG 2

Relationships between change from baseline in log₁₀ CFU and gepotidacin free-drug plasma AUC/MIC ratio for six S. aureus isolates (A) and six S. pneumoniae isolates (B), with fitted functions based on the Hill-type models overlaid on the observed data. The r² value for both these relationships was 0.925. The horizontal lines represent no net change from baseline. The observed data for each isolate are represented by a different symbol, with the fitted function overlaid.

FIG 3

Relationships between log₁₀ CFU and time overlaid with the free-drug plasma concentration-versus-time profiles for gepotidacin doses evaluated and the associated PAE for S. aureus (A) and S. pneumoniae (B) using the murine thigh infection model.