Elenbecestat (E2609) is a BACE inhibitor primarily metabolized by carboxylesterase 2 (CES2) and to lesser extent by CYP3A. Drug-drug interaction studies assessed the effects of itraconazole (strong CYP3A and CES2 inhibitor), rifampin (strong CYP3A inducer), and donepezil on elenbecestat pharmacokinetics, as well as the effects of elenbecestat on digoxin (Pgp substrate) pharmacokinetics. This open label study in healthy adult subjects was conducted in 3 parts. Part A: subjects received a single oral dose of elenbecestat 50 mg on day 1; from day 6 to 20, subjects received daily doses of either itraconazole 200 mg or rifampin 600 mg; with a second dose of elenbecestat 50 mg on day 14. Part B: subjects received digoxin 0.25 mg on day 1, elenbecestat 50 mg/day from day 7 to 20, and a second digoxin dose at day 14. Part C: a 3-way crossover study in which each subject received a single dose of elenbecestat 50 mg, elenbecestat 50 mg in combination with donepezil 10 mg, and elenbecestat 50 mg dosed 2 hours before donepezil 10 mg, according to a randomized treatment sequence with ≥21-day washout between treatments. Pharmacokinetic assessments of drugs, including elenbecestat and metabolites M1, M2, and M5, were conducted. Co-administration of elenbecestat and itraconazole resulted in increases in elenbecestat Cmax, AUC(0-inf), and t1/2 compared with administration of elenbecestat alone (Figures). The Cmax of all elenbecestat metabolites decreased with itraconazole co-administration. Co-administration of elenbecestat and rifampin resulted in relatively no change in Cmax or t1/2, a minor decrease in AUC(0-inf), along with pronounced decreases in M2 and M5. In Part B, elenbecestat and digoxin co-administration increased digoxin Cmax slightly, but no changes in overall systemic exposure (AUC) were observed. Co-administration of elenbecestat and donepezil at the same time resulted in non-clinically meaningful increases in Cmax and AUC(0-inf). However, no notable changes in elenbecestat exposure occurred when administered 2 hours before donepezil. Results indicate that itraconazole's interaction was primarily due to CES2 inhibition, therefore, no restrictions or dose adjustments are warranted for elenbecestat when co-administered with CYP3A inhibitors. Furthermore, no dose adjustments are necessary for elenbecestat when co-administered with Pgp substrates or donepezil. The effect of co-administered drugs on elenbecestat pharmacokinetics (expressed as 90% CI of geomean). Donepezil administered * concomitantly or **2 h postdose with elenbecestat Horizontal axis shows fold change in Cmax and AUC relative to control (elenbecestat alone). Note: Generic name elenbecestat is not fixed at this time. The effect of elenbecestat on pharmacokinetics of digoxin (expressed as 90% CI of geomean).