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.
Hum Psychopharmacol
; 32(1)2017 01.
Article
in En
| MEDLINE
| ID: mdl-28120486
ABSTRACT
OBJECTIVE:
Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor.METHODS:
In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF). Effect of BI 409306 on CSF cGMP levels was evaluated, and adverse events (AEs) were monitored.RESULTS:
In all enrolled subjects (N = 20), plasma BI 409306 concentration increased rapidly (median tmax 0.75-1.25 hr) followed by rapid increases in CSF (median tmax 1.5-2.0 hr). Maximum CSF cGMP concentrations were achieved within 2 to 5 hr, declining to baseline levels 10 to 14 hr after dosing. Dose-dependent increases in plasma and CSF exposure and CSF cGMP were shown. BI 409306 was safe and well tolerated. Most AEs were mild to moderate in intensity and study procedure-related.CONCLUSIONS:
BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphodiesterase Inhibitors
/
3',5'-Cyclic-AMP Phosphodiesterases
/
Proof of Concept Study
Type of study:
Clinical_trials
Limits:
Adult
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Hum Psychopharmacol
Journal subject:
PSICOFARMACOLOGIA
Year:
2017
Type:
Article
Affiliation country:
Germany