PMID- 28120486
OWN - NLM
STAT- MEDLINE
DCOM- 20171129
LR  - 20220318
IS  - 1099-1077 (Electronic)
IS  - 0885-6222 (Linking)
VI  - 32
IP  - 1
DP  - 2017 Jan
TI  - 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.
LID - 10.1002/hup.2569 [doi]
AB  - 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 t(max) : 0.75-1.25 hr) followed by rapid 
      increases in CSF (median t(max) : 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.
CI  - Copyright (c) 2017 John Wiley & Sons, Ltd.
FAU - Boland, Katja
AU  - Boland K
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Moschetti, Viktoria
AU  - Moschetti V
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
FAU - Dansirikul, Chantaratsamon
AU  - Dansirikul C
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Pichereau, Solen
AU  - Pichereau S
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Gheyle, Lien
AU  - Gheyle L
AD  - Clinical Research, SGS, Life Science Services, Antwerpen, Belgium.
FAU - Runge, Frank
AU  - Runge F
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Zimdahl-Gelling, Heike
AU  - Zimdahl-Gelling H
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Sand, Michael
AU  - Sand M
AD  - Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - England
TA  - Hum Psychopharmacol
JT  - Human psychopharmacology
JID - 8702539
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (PDE9A protein, human)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors/*metabolism
MH  - Administration, Oral
MH  - Adult
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Phosphodiesterase Inhibitors/*administration & dosage/*pharmacokinetics
MH  - *Proof of Concept Study
MH  - Young Adult
OTO - NOTNLM
OT  - Alzheimer disease
OT  - PDE inhibitor
OT  - PDE9A
OT  - cGMP
OT  - schizophrenia
EDAT- 2017/01/26 06:00
MHDA- 2017/12/01 06:00
CRDT- 2017/01/26 06:00
PHST- 2016/07/14 00:00 [received]
PHST- 2016/11/14 00:00 [revised]
PHST- 2016/12/06 00:00 [accepted]
PHST- 2017/01/26 06:00 [entrez]
PHST- 2017/01/26 06:00 [pubmed]
PHST- 2017/12/01 06:00 [medline]
AID - 10.1002/hup.2569 [doi]
PST - ppublish
SO  - Hum Psychopharmacol. 2017 Jan;32(1). doi: 10.1002/hup.2569.