Single-dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers [Pharmacology]

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 the absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed with a T_max between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg, and less than dose proportionally between 800 and 4000 mg. Urinary excretion of unchanged zoliflodacin was >5.0% of the total dose. In the fed state, absorption was delayed (T_max 4 h), accompanied by an increase in the AUC at 1500 and 3000 mg doses. In the ADME study (3000 mg PO), the PK profile of zoliflodacin had similar exposure (AUC and C_max) to the ascending dose study and a median T_max of 2.5 hours. 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 the safety, PK, and the PK/PD targets, a dosage regimen was selected for evaluation in a Phase 2 study in urogenital gonorrhea.

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