[P3–014]: INVESTIGATION OF PHARMACOKINETIC DRUG‐DRUG INTERACTION FOLLOWING ORAL ADMINISTRATION OF BI 409306 AND DONEPEZIL IN HEALTHY SUBJECTS

BI 409306 is a potent, selective phosphodiesterase-9 (PDE9) inhibitor being developed for treatment of cognitive impairment associated with Alzheimer's disease (AD). Donepezil is a specific, reversible inhibitor of acetylcholinesterase indicated for treatment of mild to moderate AD. As co-medication with both drugs is a reasonable expectation for patients with AD, this study investigated potential drug-drug interactions (DDI) between BI 409306 and donepezil. This Phase I, clinical study investigated the effect of multiple-dose donepezil 10 mg at steady state on single-dose pharmacokinetics (PK) of BI 409306 25 mg (Part I; one fixed-sequence, open-label design) and multiple-dose BI 409306 100 mg on single-dose PK of donepezil 5 mg (Part II; randomized, open-label, two-way crossover design) in healthy subjects. Part II randomized subjects (1:1) into two treatment sequences; donepezil then donepezil + BI 409306, or vice versa. Primary endpoints were area under the concentration-time curve from 0 hours to the last quantifiable time-point (AUC0-tz) and maximum concentration (Cmax) of BI 409306 (Part I) and donepezil (Part II) in plasma; secondary endpoints were AUC from 0 hours extrapolated to infinity (AUC0-∞) of BI 409306 (Part I) and donepezil (Part II). Safety was assessed by monitoring adverse events (AEs). Overall, 31/32 subjects completed the study. Co-administration of donepezil 10 mg with BI 409306 25 mg (Part I), versus BI 409306 25 mg only, had no clinically relevant effect on exposure of BI 409306 (adjusted geometric mean [gMean] ratios [90% confidence interval (CI)]: Cmax, 100.82% [81.9%, 124.2%]), AUC0-tz, 99.95% [89.5%, 111.6%] or AUC0-∞, 100.01% [89.5%, 111.7%]). BI 409306 100 mg co-administered with donepezil 5 mg (Part II) had no effect on Cmax, AUC0-tz or AUC0-∞ of donepezil (adjusted gMean ratios [90% CI]; 113.08% [106.4%, 120.2%]; 100.84% [97.6%, 104.2%] and 98.38% [93.4%, 103.6%], respectively). Mild/moderate drug-related AEs, either to BI 409306, donepezil or to both, were reported in 28/32 (87.5%) subjects; all resolved by study end. No serious AEs or AEs of special interest occurred. Present PK results demonstrate no DDI between BI 409306 and donepezil at the doses tested. BI 409306 was well tolerated, consistent with previous observations.

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