Manager, Quantitative Clinical Pharmacology GlaxoSmithKline plc Collegeville, Pennsylvania, United States
Statement of Purpose: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, including those resistant to current antibiotics. Phase 3 clinical studies are currently underway to assess gepotidacin in uncomplicated urinary tract infection (NCT04020341, NCT04187144) and uncomplicated urogenital gonorrhea (NCT04010539). The study objective was to assess the pharmacokinetics (PK), safety, and tolerability of a single oral dose of 1,500 mg gepotidacin and 2 × 3,000 mg doses of gepotidacin in healthy adult Japanese participants, to evaluate the effect of a standard Japanese meal on the PK of the to-be-marketed formulation, and to compare results with those of Western participants.
Description of Methods & Materials: This was a double-blind, placebo-controlled, randomized study of gepotidacin (10 active: 2 placebo) administered as 1,500 mg (2 × 750 mg tablets) single oral dose under fed and fasted conditions (Periods 1 and 2) in a randomized sequence, and as 2 × 3,000 mg doses given 12 hours apart under fed conditions (Period 3) in healthy Japanese participants. Plasma and urine PK samples were collected for gepotidacin bioanalysis and standard noncompartmental pharmacokinetic parameters were calculated. Geometric least squares (LS) mean ratios (fed/fasted) were determined using a mixed-effects model. Data for Western participants was sourced from 3 additional cohorts included in this study.
Data & Results: This study enrolled 14 healthy Japanese participants in the safety population and included 11 in PK analyses. Comparable plasma concentrations were observed following administration of a single 1,500 mg gepotidacin dose under fed and fasted conditions, with median time to maximum plasma concentration (tmax) of 2.00 and 1.50 hours, respectively. Gepotidacin plasma area under the concentration-time curve (AUC) were similar between fed and fasted conditions with geometric LS mean fed/fasted ratios (90% confidence interval [CI]) of 1.09 (0.987, 1.21) and 1.10 (0.991, 1.21) for AUC0–t and AUC0–∞ respectively, while maximum plasma concentration (Cmax) 1.05 (0.824, 1.34) was slightly higher with an upper limit 90% CI of 1.34 (See Table 1). Mean urine concentrations were ≥ 4 µg/mL (minimum inhibitory concentration at which 90% of isolates are inhibited [MIC90] for fluoroquinolone-resistant subsets of Escherichia coli) and were maintained for 24–48 hours post-dose after single 1,500 mg dose under fed conditions. Geometric mean Cmax was approximately dose proportional from the 1,500 mg to 3,000 mg dose. Following administration of 2 × 3,000 mg gepotidacin doses given 12 hours apart under fed conditions, median tmax was 2 hours; minimal accumulation was observed after the second dose. Comparable plasma AUC but slightly higher Cmax (average 7–30%) and slightly lower urine AUC (average 11–18%) were observed in Japanese participants compared with Western (Caucasian) participants. AEs were experienced by 36% of participants, primarily in the gastrointestinal system organ class; diarrhea and nausea were most commonly-reported adverse events (both 21%).
Interpretation, Conclusion or Significance: Overall, these data indicate the analyzed doses are supportive of gepotidacin use in clinical studies in Japanese patients with uncomplicated urinary tract infection or uncomplicated urogenital gonorrhea.
