e14097 Background: Entospletinib (ENTO), a Syk inhibitor, has shown clinical activity in R/R CLL subjects. In vitro, ENTO inhibited OATP1B1/1B3, BCRP, P-gp and UGT1A1; ENTO metabolism is mediated by CYP2C9 and CYP3A. These studies evaluate the drug interaction (DDI) profile and mass balance (MB) of ENTO. Methods: Healthy subjects received ENTO alone, or with cobicistat (COBI; CYP3A inhibitor), rifampin (RIF; CYP3A inducer), fluconazole (FLU; CYP2C9/CYP3A inhibitor), rosuvastatin (ROS; OATP1B1/1B3, BCRP substrate) or digoxin (DIG, P-gp substrate). For the MB study, healthy subjects received a single dose of ENTO containing [14C]-labeled ENTO. Results: DDI results are shown below. ENTO was extensively metabolized to 14 metabolites in the MB study; ~91% and ~2% of the dose was recovered in feces and urine, respectively. The majority of circulating radioactivity was associated with unchanged ENTO. ENTO was generally well tolerated in these studies. Conclusions: Co-administration with strong CYP3A inducers may decrease ENTO exposures; strong CYP3A inhibitors do not significantly affect ENTO exposures. ENTO may increase exposures of OATP1B1/1B3/BCRP and P-gp substrates. ENTO is extensively metabolized and excreted in feces. Comparison Dose aParameter bGMR (90% CI) ENTO+COBI vs ENTO ENTO: 100 mg BID COBI: 150 mg QD ENTO Cmax ENTO AUCtau 108 (97, 121) 117 (106, 130) ENTO+RIF vs ENTO ENTO: 400 mg BID RIF: 600 mg QD ENTO Cmax ENTO AUCtau 42 (36, 49) 29 (25, 34) ENTO+FLU vs ENTO ENTO: 100 mg BID FLU: c400/200 mg QD ENTO Cmax ENTO AUCtau 132 (119, 147) 141 (127, 157) ROS+ENTO vs ROS dROS: 10 mg SD ENTO: 400 mg BID ROS Cmax ROS AUCinf 368 (298, 456) 381 (316, 460) DIG+ENTO vs DIG dDIG: 0.5 mg SD ENTO: 400 mg BID DIG Cmax DIG AUCinf 139 (114, 169) 138 (128, 148) a Cmax (ng/mL); AUC (ng.h/mL) bGMR: geometric mean ratio, CI: confidence interval c 400 mg dose Day 1 then 200 mg QD d SD: single dose