Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented; a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free base roller compacted (RC) tablets, free base high shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80 to 1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher compared to the reference (ratio: 1.15; 90% CIs: 1.0113, 1.3047). In the healthy adult (n=16) and adolescent (n=17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose, 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo. Single-dose mean Cmax was ∼27% higher in adolescents versus adults and area under the concentration-time curve (AUC) was comparable in both populations. After 2 doses were administered, mean Cmax was similar for both ages and mean AUC was ∼35% higher in adolescents versus adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar in both ages. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well-characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy.