Novel Bacterial Topoisomerase Inhibitor Gepotidacin Demonstrates Absence of Fluoroquinolone-Like Arthropathy in Juvenile Rats

Abstract

Fluoroquinolone use in children is limited due to its potential toxicity and negative effects on skeletal development, but the actual effects/risks of fluoroquinolones on bone growth and the mechanisms behind fluoroquinolone-driven arthropathy remain unknown. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic with a unique mechanism of action that is not anticipated to have the same risks to bone growth as those of fluoroquinolones. Gepotidacin is in phase III clinical development for uncomplicated urinary tract infections (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144) and urogenital gonorrhea (ClinicalTrials.gov identifier NCT04010539) in adults and adolescents ≥12 years of age. To inform arthropathy and other potential toxicity risks of gepotidacin in pediatric studies, this nonclinical study assessed oral gepotidacin toxicity in juvenile rats from postnatal day (PND) 4 to PND 32/35 (approximately equivalent to human ages from newborn to 11 years), using both in-life assessments (tolerability, toxicity, and toxicokinetics) and terminal assessments (necropsy with macroscopic and microscopic skeletal femoral head and/or stifle joint examinations). Gepotidacin doses of ≤300 mg/kg of body weight/day were well tolerated from PND 4 to PND 21, and higher doses of ≤1,250 mg/kg/day were well tolerated from PND 22 when the dose levels were escalated to maintain systemic exposure levels up to PND 35, with no observed treatment-related clinical signs, effects on mean body weight gain, or macroscopic findings on articular surfaces. A dose of 1,000 mg/kg/day was not tolerated during the dosing period from PND 4 to 21, with effects on body weight gain, fecal consistency, and body condition. Microscopic effects on articular surfaces were evaluated after 32 days of gepotidacin treatment at the highest tolerated dose. After 32 days of treatment with the highest tolerated gepotidacin dose of 300/1,250 mg/kg/day (systemic concentrations [area under the curve {AUC} values] of 93.7 μg · h/mL [males] and 121 μg · h/mL [females]), no skeletal effects on articular surfaces of the femoral head or stifle joint were observed. The absence of treatment-related clinical signs and arthropathy in juvenile rats provides evidence to support the potential future use of gepotidacin in children.

Keywords: antibiotic resistance; arthropathy; children; drug safety; drug toxicity; fluoroquinolone; gepotidacin; juvenile rat; nonclinical study; pediatric; preclinical study.

Conflict of interest statement

The authors declare a conflict of interest. C.F., S.B.L., D.J.S., N.P., S.J., and D.N.-F. are employees of GSK. J.M.C.R., L.M.P., S.A.L., and E.D. are former employees of GSK.

Figures

FIG 1

Round 1 mean area under the curve from time zero to the last measurable concentration (AUC0–t) values in males (A) and females (B) on postnatal day (PND) 13 and PND 21 by gepotidacin dose showing a marked decrease in exposure at PND 21 compared to PND 13. The days on which samples were collected are marked in black text. aFor the purpose of calculating the AUC0–t, the concentrations at time zero were assigned with the concentrations at 24 h. Female parameters for a 1-mg/kg/day gepotidacin dose on PND 13 and male and female parameters for 1- and 10-mg/kg/day gepotidacin doses on PND 21 could not be calculated due to limited measurable data.

FIG 2

Round 2 mean area under the curve from time zero to the last measurable concentration (AUC0–t) values in males (A) and females (B) on postnatal day (PND) 13, PND 22, and PND 35 by gepotidacin dose with dose escalation on PND 22 to maintain systemic exposure as much as possible across the age range. The days on which samples were collected are marked in black text. aFor the purpose of calculating the AUC0–t, the concentrations at time zero were assigned with the concentrations at 24 h.

FIG 3

Round 3 toxicokinetics of mean area under the curve from time zero to the last measurable concentration (AUC0–t) values in males (A) and females (B) on postnatal day (PND) 22 and PND 32 by gepotidacin dose with dose escalation on PND 21 to maintain exposure levels and separation between dose groups as much as possible at the potential maximum tolerated doses. The days on which samples were collected are marked in black text. Additional lines show approximate AUC clinical exposures for uncomplicated urinary tract infection (uUTI) and urogenital gonorrhea (GC) indications (40 μg · h/mL [orange] and 85 μg · h/mL [green], respectively). aFor the purpose of calculating the AUC0–t, the concentrations at time zero were assigned with the concentrations at 24 h.

FIG 4

Normal microscopic appearance of articular cartilage of the distal femur (A) and proximal tibia (B) from control juvenile rats (left) and high-dose gepotidacin (300/1,250 mg/kg/day)-treated juvenile rats (right) dosed from postnatal day (PND) 4 to PND 32, with necropsy on PND 33. Arrows indicate articular cartilage. A subtle tiling artifact in the white background (of the top right panel) was contained within the digital image file and considered related to computer stitching of images by the Aperio Scanscope instrument (Leica Biosystems, Deer Park, IL, USA).

FIG 5

Study design. All rat pups were dosed directly by oral gavage with a gepotidacin suspension (1% aqueous methylcellulose, with a viscosity of 400 cP [2% solution in water]) at a dose volume of 5 mL/kg based on daily body weight. In-life observations included clinical observations and recording of body weight. PND, postnatal day.