First‐in‐human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males

Abstract

AimsThe aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)‐2C19.MethodsThe present randomized, double‐blind, placebo‐controlled, single‐centre study evaluated single rising doses of BI 409306 (0.5–500 mg) administered as a tablet or oral solution to EMs or PMs.ResultsOf 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20–30 min) after administration and mostly resolved within 1–2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax) was reached <1 h after drug administration, and the half‐life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2–2.3‐fold higher, and the area under the plasma concentration–time curve over the time interval 0 extrapolated to infinity was 4.1–5.0‐fold higher compared with EMs.ConclusionsIn healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

A phase I, randomized, proof‐of‐clinical‐mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers

“…Results of this study assessing the PK and PD of single doses of BI 409306 in healthy men provide evidence for the proof of clinical mechanism for this novel PDE9A inhibitor. BI 409306 was rapidly absorbed, distributed, and eliminated after administration of single doses ranging from 25 to 200 mg. PK data are in agreement with results from a previous trial evaluating single rising doses in healthy male volunteers (Moschetti et al, ) and other studies wherein BI 409306 was orally administered once daily over 14 days in young and elderly healthy subjects (Moschetti et al, ; Wunderlich et al, ), young CYP2C19 poor metabolizers (Wunderlich et al, ), and in patients with schizophrenia (Brown et al, ).…”

“…Selection of BI 409306 doses was supported by in vitro IC 50 data of BI 409306, the human PK data after single‐dose administration of BI 409306 (Moschetti et al, ), and the literature data of CSF cGMP in humans (Nicholas et al, ). The selected dose in this study was expected to provide the wide range of response (increase of CSF cGMP) and, hence, allowed demonstration of the proof of clinical mechanism for the effect of BI 409306.…”

“…The novel PDE9A inhibitor BI 409306 was shown to be a potent and selective PDE9A inhibitor in rats and reversed dizocilpine‐induced memory deficits and improved memory performance in mice (Dorner‐Ciossek, Giovannini, & Rosenbrock, ; Rosenbrock et al, ). BI 409306 demonstrated generally favorable safety and tolerability in a first‐in‐human trial evaluating single rising doses of BI 409306 in healthy male volunteers; most commonly reported adverse events (AEs) were headache (10.1%), photopsia (flashing lights; 7.6%), and photophobia (increased sensitivity to light; 3.8%), all of which were of mild to moderate intensity (Moschetti et al, ). Another study, in young and elderly healthy volunteers, tested multiple rising doses of BI 409306 given once or twice daily for 14 days and found that most of the AEs were mild in intensity, although there was a dose‐dependent increase in eye disorders (Moschetti et al, ; Wunderlich et al, ).…”

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…[97]). Efficacy studies are currently being conducted in Phase II clinical trials for both AD and schizophrenia (ClinicalTrials.gov Identifier: NCT02337907 and NCT02281773).…”

“…Consequently, a specific cognitive process could be temporarily targeted only when needed. The recent Boehringer compound BI 409,306 has a short half-life of 0.99-2.71 h in humans [97]. This would open opportunities for timed treatment of specific cognitive processes.…”