期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 20, 期 2, 页码 80-87出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2009.10.005
关键词
Neurokinin-1 receptors; Substance P; Social anxiety disorder; Positron emission tomography; Randomized clinical trial
资金
- Eli Lilly and Company (Lilly), Indianapolis, IN
The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [(11)C]GR205171 was used healthy volunteers receiving 1-100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of >30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients' suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 (N=77), placebo (N=74), or 20 mg/d paroxetine (N=38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted. (C) 2009 Elsevier B.V. and ECNP. All rights reserved.
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