Abstract A113: Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects
Authors: Dai Xiaoshu , Karol Michael D , Hitron Matthew , Hard Marjie , Blanchard J Evan , Eraut Nicola , Rich Natalie , Gufford Brandon 
Published: March 2020

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 and 7.9 L/h, respectively. All subjects experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild (grade 1) and the majority were assessed as related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders and, of these, diarrhea was reported most frequently and generally started within 4.5–5.0 h postdose and resolved without treatment. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Conclusions: 14C-napabucasin is primarily excreted through feces. 14C-napabucasin underwent extensive metabolism to yield M1 as the sole major circulating metabolite. No uniquely human or disproportionate metabolite was quantified. A single oral 240-mg dose of napabucasin was tolerated in healthy male subjects.

Citation Format: Xiaoshu Dai, Michael D Karol, Matthew Hitron, Marjie Hard, J Evan Blanchard, Nicola Eraut, Natalie Rich, Brandon Gufford. Mass balance and pharmacokinetics of an oral dose of 14C-napabucasin in healthy adult male subjects [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A113. doi:10.1158/1535-7163.TARG-19-A113