Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects

Abstract

Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial DNA replication by a distinct mechanism of action. We report the pharmacokinetics (PKs), safety, and tolerability of gepotidacin following single or multiple ascending doses. Studies 1 and 2 were randomized, single-blind, placebo-controlled trials in healthy adults aged 18-60 years, who received single (study 1 [NCT02202187]; 100-3000 mg) or repeat (study 2 [NCT01706315]; 400 mg twice daily to 2000 mg thrice daily) ascending doses of gepotidacin. Study 3 (NCT02045849) was an open-label, three-part, study in healthy adults; here, we report on part 3, a two-period, repeat-dose, crossover study. Healthy elderly participants received repeat 1500 mg gepotidacin twice daily with or without a moderate-fat meal. Primary end points were PKs (studies 1 and 2) and safety (studies 1 and 3 part 3). Gepotidacin PK parameters were comparable across all ages and were dose proportional. In all studies, gepotidacin was readily absorbed with median time to maximum concentration observed ranging from 1.0 to 4.0 h across all doses. Median apparent terminal phase half-life was consistent across studies and doses (range: 5.97-19.2 h). Steady-state was achieved following repeated dosing for 3-5 days; gepotidacin PK parameters were time invariant after repeated oral dosing. A moderate-fat meal did not affect gepotidacin PK parameters. Gepotidacin was generally well-tolerated, with no drug-related serious adverse events reported. Collectively, these PK and safety data across a wide range of doses in healthy participants aged greater than or equal to 18 years support the development of gepotidacin in further clinical studies.

FIGURE 1

Simplistic representation showing fluoroquinolones and triazaacenaphthylene (e.g., gepotidacin) antibiotics bind to different sites on DNA gyrase/DNA topoisomerase IV bacterial targets. Two fluoroquinolone molecules can bind at the two separate sites of DNA cleavage on DNA gyrase (a type of topoisomerase) and DNA topoisomerase IV, by binding with the Ser84 and Glu88 residues (Staphylococcus aureus numbering of DNA gyrase) that also involve a divalent magnesium ion and water molecules. This results in stabilization of double‐stranded DNA breaks that are lethal to the bacterial cell if they are not repaired. These quinolone binding residues are most commonly mutated in fluroquinolone‐resistant clinical strains. In contrast, a single gepotidacin molecule binds to one site on DNA gyrase and topoisomerase IV through interactions with Asp83 of DNA gyrase or topoisomerase IV involving water molecule, resulting in enhancement of single‐stranded DNA breaks, which can be lethal to the bacteria.

FIGURE 2

Study design of (a) study 1 (single ascending dose, aged 18–60 years), (b) study 2 (repeat ascending doses, aged 18–60 years), and (c) study 3 part 3 (repeat dose with or without food, aged ≥65 years).

FIGURE 3

Median blood‐concentration time profile (semi‐log scale) for gepotidacin following single ascending oral doses in healthy adults aged 21–59 years (study 1) in the phamacokinetic population. Gepotidacin blood concentration‐time profile displayed bi‐phasic elimination. n = 6 per dose.

FIGURE 4

Geometric mean AUC (a) and C _max (b) concentrations for all studies and individual concentrations for participants form study 3 part 3 for C _max, normalized by dose in fasted and fed participants. Food had little effect on the rate and extent of absorption across all studies. n = 6 per dose for studies 1 and 2, and n = 15 per dose for study 3. Matched data were available for n = 12 in study 3 part 3. Study 1: single ascending dose, aged 18–60 years, 2300 mg fasted or fed; study 2: repeat ascending doses, aged 18–60 years, 1500 mg fasted or fed; study 3: repeat dose, aged ≥65 years, 1500 mg fasted or fed. In panel a, studies 1 and 2 are AUC_0–∞, study 3 is AUC_0–τ. AUC, area under the concentration‐time curve from 0 to infinity; C _max, maximum observed concentration.