Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers

Abstract

Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (Tmax) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (Tmax, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [Cmax]) similar to that of the ascending dose study and a median Tmax of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).

Keywords: ADME; Neisseria gonorrhoeae; healthy volunteers; single dose; zoliflodacin.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Geometric mean plasma concentrations of zoliflodacin (logarithmic scale) versus time curves (pharmacokinetic analysis set, n = 6).

FIG 2

Arithmetic mean (SD) zoliflodacin plasma concentration-time profiles and total radioactivity concentration-time profiles in plasma and whole blood (PK population). Assay range was 1.00 ng/ml (LLOQ) to 5,000 ng/ml.

FIG 3

Arithmetic mean (±SD) cumulative percentage of dose recovered as total radioactivity in urine and feces (PK population).

FIG 4

Representative radioactivity profiles in pooled plasma at 0 to 24 h (A), urine at 0 to 48 h (B), and feces at 24 to 96 h (C). Urine collections were obtained and pooled at 0 to 6, 6 to 12, 12 to 24, and 24 to 48 h postdose. Feces were collected and pooled at 0 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144 to 168 h postdose.

FIG 5

Collision-induced dissociation product ion spectra of zoliflodacin ([M+H]+ = 488).

FIG 6

Proposed metabolic scheme of [14C]zoliflodacin following oral administration to humans.