Citation

Brown D, Daniels K, Pichereau S, Sand M. Neurol. Ther. 2018; 7(1): 129-139.

Copyright

(Copyright © 2018, Holtzbrinck Springer Nature Publishing Group)

DOI

10.1007/s40120-017-0085-5

PMID

unavailable

Abstract

INTRODUCTION: This randomized, double-blind, parallel-group study investigated the safety, tolerability, pharmacokinetics (PK), and cognitive outcomes of BI 409306--a selective phosphodiesterase 9A (PDE9A) inhibitor--in patients with schizophrenia.

METHODS: Patients with mild-to-moderate schizophrenia were randomized (1:1:1:1) to receive BI 409306 at 25, 50, or 100 mg or placebo once daily over 14 days. The primary endpoints were safety and tolerability; the secondary endpoints were PK and cognitive outcomes.

RESULTS: Of the 40 randomized patients, 38 (95%) completed the study. Patients were predominantly male (87.5%; mean age, 40.2 years). After a single dose, Cmax was reached within 30-45 min. The geometric mean (gMean) Cmax and AUC0-∞ ranged from 138 to 998 nmol/L and 217 to 2020 nmol∙h/L, respectively. Elimination was rapid (gMean t1/2 range 1.10-1.85 h). After multiple doses, Cmax,ss was reached within 1 h; elimination was similar to that observed after a single dose. Total exposure at steady state and after a single dose were similar (accumulation ratio range: AUC, 0.758-1.13 and Cmax, 0.768-1.40). No deaths, adverse events (AEs) leading to discontinuation, or serious AEs were observed. Treatment-emergent AEs were mild, with no apparent dose-related trends. There was no worsening of schizophrenia symptoms (Positive and Negative Syndrome Scale) and no trends in suicidality (Columbia Suicide Severity Rating Scale). The Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) showed no effect on cognitive function.

CONCLUSION: Administration of BI 409306 in patients with mild-to-moderate schizophrenia resulted in satisfactory safety and tolerability. BI 409306, PK was characterized by rapid absorption, monophasic to biphasic elimination, and minor accumulation with multiple dosing. Trial Registration: ClinicalTrials.gov identifier NCT01892384. Funding: Boehringer Ingelheim Pharma GmbH & Co. KG. © 2017, The Author(s).

Language: en

Keywords

Safety; adult; human; cognition; female; male; Schizophrenia; schizophrenia; randomized controlled trial; visual impairment; Tolerability; vomiting; controlled study; neuroleptic agent; clinical article; unclassified drug; area under the curve; double blind procedure; headache; physical examination; anxiety disorder; drug safety; placebo; mental patient; backache; drug tolerability; nausea; tremor; Pharmacokinetics; agitation; DSM-IV; neuropsychological test; tooth pain; laboratory test; dizziness; steady state; Article; tooth infection; gastroesophageal reflux; outcome assessment; treatment duration; Clinical Global Impression scale; blurred vision; Positive and Negative Syndrome Scale; phosphodiesterase inhibitor; Phosphodiesterase inhibitor; Phase I; cytochrome P450 2C19; musculoskeletal pain; visual field defect; elimination half-life; pharmacokinetic parameters; maximum concentration; accumulation ratio; bi 409306; BI 409306; Brief Visuospatial Memory Test Revised; Cognitive outcome; furunculosis; Hopkins verbal learning test; PDE9A