Abstract A113: Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects

• Published in: Molecular cancer therapeutics 2019-12, Vol.18 (12_Supplement), p.A113-A113
• Main Authors: Dai, Xiaoshu, Karol, Michael D, Hitron, Matthew, Hard, Marjie, Blanchard, J Evan, Eraut, Nicola, Rich, Natalie, Gufford, Brandon
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-19-A113

Introduction: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. The primary objectives of this phase 1, open-label study in healthy male subjects were to characterize the absorption, metabolism, and excretion of 14C-napabucasin and to determine the pharmacokinetics of 14C-napabucasin and relevant metabolites in plasma, urine, and feces. The secondary objective was to assess safety and tolerability of napabucasin. Methods: Healthy male adult (age 18–45 years) subjects were eligible to receive a single oral 240-mg dose of napabucasin containing ~100 μCi of 14C-napabucasin. Blood, urine, and feces were collected up to 264 hours (h; 11 days) postdose. Whole blood, plasma, urine, fecal, and expired air samples were assayed for total radioactivity (TR). Plasma, urine, and fecal samples were assayed for napabucasin and metabolites. Results: Overall, 8 subjects (mean [range] age 29 [23–39] years) were enrolled. The mean TR recovered was 81.1%. In general, elimination of 14C-napabucasin was predominantly via feces (57.2%), to a lesser extent via urine (23.8%), and was negligible in expired air. Most (76.0%) recovery was within 48 h postdose. 14C-napabucasin was rapidly absorbed (median time to peak concentration 2.8 h) and underwent extensive reductive metabolism to yield dihydro-napabucasin (M1), the sole major circulating metabolite. Systemic exposure to 14C-napabucasin was higher than M1, and M1 plasma concentration versus time profiles generally mirrored 14C-napabucasin. Similar arithmetic mean half-lives for 14C-napabuscasin and M1 (7.9 h and 7.1 h, respectively) suggest that the rate of formation of the reduced metabolite is rate limiting. The TR whole blood:plasma ratio of 0.4 indicated that circulating drug-related compounds were essentially confined to plasma. Four minor metabolites were identified but accounted for ≤7.0% of TR in plasma. Consistent with preclinical animal models, no uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites. These data suggest that 14C-napabucasin was mainly cleared by reductive metabolism and, to a lesser extent, by renal elimination.  14C-napabucasin and M1 recovered in urine accounted for 13.2% and 9.6% of the administered dose, respectively. Apparent renal clearance of 14C-napabucasin and M1 were 8.1 L/h