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

Abstract

Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC). Gepotidacin is currently in clinical development for the treatment of uUTIs and other infections. In this article, we review data for gepotidacin from nonclinical studies, including in vitro activity, in vivo animal efficacy, and pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models that informed dose selection for phase III clinical evaluation of gepotidacin. Based on this translational package of data, a gepotidacin 1,500-mg oral dose twice daily for 5 days was selected for two ongoing, randomized, multicenter, parallel-group, double-blind, double-dummy, active-comparator phase III clinical studies evaluating the safety and efficacy of gepotidacin in adolescent and adult female participants with uUTIs (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144).

Keywords: acute cystitis; acute uncomplicated cystitis; antibacterial; dose selection; gepotidacin; pharmacodynamics; pharmacokinetics; uncomplicated urinary tract infection.

Conflict of interest statement

The authors declare a conflict of interest. All authors report employment with, and stock/share ownership in, GlaxoSmithKline plc. at the time of study. M.H. is currently employed by Adios Pharmaceuticals, Cambridge, MA. C.T. is currently employed by Gan and Lee Pharmaceuticals, Bridgewater, NJ. A.B. is currently employed by Global Blood Therapeutics, San Francisco, CA. E.F.D. is currently employed by Boston Pharmaceuticals, Cambridge, MA.

All authors report employment with, and stock/share ownership in, GlaxoSmithKline plc at the time of the study.

Figures

FIG 1

Frequency distribution of GEP MICs (micrograms per milliliter) against 1,010 E. coli isolates, including those resistant to levofloxacin (25.9% resistant isolates), fosfomycin (0.3%), nitrofurantoin (0.6%), or trimethoprim-sulfamethoxazole (37.7%) or positive for the ESBL phenotype (17.7%) (15). The ESBL phenotype was based on a ceftriaxone MIC of ≥2 μg/mL, according to CLSI guidelines (15, 33). (Based on data from reference .)

FIG 2

Reductions in bacterial burdens of four strains of multidrug-resistant E. coli after 4 days of treatment in rat kidneys (A) and time course of the efficacy of gepotidacin (GEP) at 1,500 mg q12h in rat kidneys (B) (25). Rats were infected by injection of E. coli directly into each kidney. At 2 h postinfection, the administration of gepotidacin was initiated using a continuous i.v. infusion into preimplanted jugular catheters. Infusion rates were controlled by preprogrammed infusion pumps, and flow rates varied over time to create systemic PK profiles in rats that mimicked systemic PK profiles measured in humans (both corrected for differences in protein binding); mean PK profiles from human oral doses of 800 mg and/or 1,500 mg q12h were tested. *, P < 0.05; **, P < 0.01 (representing a statistically significant reduction versus the 2-h baseline controls). Note that gepotidacin had previously demonstrated MICs of 2 to 4 μg/mL against the four strains of multidrug-resistant E. coli. LLQ, lower limit of quantification; LVX, levofloxacin; PO, oral; q12h, every 12 h; q24h, every 24 h. (Redrawn from reference .)

FIG 3

Relationship between gepotidacin exposure and change in log10 CFU per milliliter from the baseline of the gepotidacin-resistant subpopulation for E. coli NCTC 13441 on day 10. (Redrawn from reference .)

FIG 4

Median gepotidacin urine concentration-time plot following oral administration of gepotidacin at 1,500 mg BID from the phase IIa uUTI study (ClinicalTrials.gov identifier NCT03568942) in 22 participants with uUTIs (8). The lower limit of quantification, represented by the dashed line, was 1.00 μg/mL. Data are plotted by the planned relative midpoint time for each interval. Notes that based on trough predose plasma concentrations of gepotidacin and statistical analysis, plasma steady state was achieved by day 3. One participant received nine doses of the study treatment. The second dose of the study treatment was not administered due to a study treatment administration protocol deviation by the site. (Redrawn from reference .)