BI 409306, A Novel PDE9 Inhibitor, Crosses the Blood–Brain Barrier and Triggers Dose- and Concentration-Dependent Increases in Cerebrospinal Fluid (CSF) Cyclic Guanosine Monophosphate (cGMP) Levels

Poster B78, Friday, October 21, 11:30 am - 1:00 pm, Le Baron

Michael Sand1, Chantaratsamon Dansirikul2, Solen Pichereau2, Lien Gheyle3, Katja Boland2; 1Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA, 2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany, 3SGS Life Science Services – Clinical Research, Antwerp, Belgium

Purpose: In the neurodevelopmental hypothesis of schizophrenia, impaired glutamatergic transmission in (pre-) frontal cortical and limbic areas of the brain may contribute to faulty synaptic pruning during adolescence and early adulthood. Increasing cGMP levels may enhance glutamatergic signalling, thereby strengthening synaptic plasticity. This study assessed exposure of BI 409306, a potent, selective phosphodiesterase 9 inhibitor, in CSF and plasma, and evaluated the effects of BI 409306 on CSF cGMP levels. Materials and Methods: In this parallel-group, double-blind study, healthy male volunteers were randomised to one of four BI 409306 doses (25, 50, 100 and 200 mg) or placebo (each group, n=4). Results: All subjects completed the trial (mean age, 37.9 years [n=20]). BI 409306 concentration increased rapidly in both plasma and CSF (median time to maximum concentration: 0.75−1.25 h vs 1.5−2.0 h for plasma and CSF, respectively). The maximum BI 409306 concentration in CSF was 28.3% of the maximum plasma concentration. CSF cGMP levels increased with rising BI 409306 doses, reaching maximum levels within 2−5 h, and declining to approximately baseline levels 10−14 h post-drug administration. BI 409306 was well tolerated, with no clustering of adverse events (AEs), no dose-dependent increases in number or intensity of AEs, no deaths, and no serious AEs. No clinically relevant findings were reported for laboratory parameters, electrocardiogram recordings, vital signs or visual tests. Conclusion: Following single-dose administration, BI 409306 (doses of 25−200 mg) crossed the blood–brain barrier and triggered dose- and concentration-dependent increases in CSF cGMP levels. Funding: Boehringer Ingelheim (Study 1289.3; NCT01493570).

Topic Area: Psychopharmacology

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