The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers.

Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days. Trial 3 randomised Chinese and Japanese extensive metabolisers of CYP2C19 to receive single doses (SD) of BI 409306 25, 50, 100 mg or placebo and Chinese (PM) to SD of BI 409306 100 mg or placebo (Part 1). Japanese PM received SD of BI 409306 100 mg or placebo (Day 1) followed by BI 409306 100 mg or placebo OD for 7 days after a 48-hour washout period (Part 2). Reported adverse events (AE) were mild-to-moderate intensity and increased with BI 409306 dose. Eye disorders were most commonly reported (Trial 1: 40.0-41.7%, Trial 2: 29.2-37.5%, Trial 3: 18.2-66.7%) and increased with dose and systemic exposure. PM reported more AEs than other treatment groups, corresponding to higher systemic exposure to BI 409306. Systemic exposure to BI 409306 produced dose-dependent increases and was slightly greater in elderly versus young subgroups (Trial 1). Steady state was achieved by Day 2-3. Overall, BI 409306 demonstrated good safety, tolerability and minor accumulation after multiple dosing.