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

Abstract

Aims: The 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.

Methods: The 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.

Results: Of 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 (C_max ) 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, C_max 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.

Conclusions: In 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.

Keywords: Alzheimer's disease; PDE9A; cognitive impairment; phosphodiesterase inhibitor; schizophrenia.

Figure 1

Putative mechanism of action of PDE9 inhibition for strengthening synaptic plasticity. AMPA‐R, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor; cGMP, cyclic guanosine monophosphate; GMP, guanosine‐5′‐monophosphate; GTP, guanosine‐5′‐triphosphate; NMDA‐R, N‐methyl‐D‐aspartate receptor; NO, nitric oxide; NOS, nitric oxide synthase; pCREB, phosphorylated cyclic adenosine monophosphate response element binding protein; PDE9, phosphodiesterase 9; sGC, soluble guanylyl cyclase

Figure 2

Study design. CYP, cytochrome P450; DG, dose group; ECG, electrocardiogram; EM, extensive metabolizers; IR, immediate release; PM, poor metabolizers; sol, oral solution

Figure 3

Patient disposition. EM, extensive metabolizers; PM, poor metabolizers; sol, oral solution; tab, tablet

Figure 4

Geometric mean drug plasma concentration–time profiles after administration of 0.5–350 mg BI 409306 to cytochrome P450 2C19‐genotyped extensive metabolizers and poor metabolizers. EM, extensive metabolizers; PM, poor metabolizers. 0.5 mg solution EM (n = 6), 5 mg solution EM (n = 6), 10 mg tablet EM (n = 6), 50 mg tablet EM (n = 6), 100 mg tablet EM (n = 5), 350 mg tablet EM (n = 6), 100 mg tablet PM (n = 6), 2 mg solution EM (n = 6), 5 mg tablet EM (n = 6), 25 mg tablet EM (n = 6), 50 mg solution EM (n = 8), 200 mg tablet EM (n = 6), 10 mg tablet PM (n = 6)