Adverse Events in Healthy Subjects Exposed to Single and Multiple Doses of LY2140023 Monohydrate

Abstract

Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple-dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects.

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects

“…An exploratory analysis of dose proportionality of plasma 2812223 PK was conducted for C max and AUC (0–∞) /AUC τ,ss using a power model fitting log e (PK parameter) against log e (dose) and subject as a random effect. Predicted ratios of dose‐normalized means, starting with the highest dose/lowest dose tested and corresponding 95% confidence intervals (CIs), were estimated.…”

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

“…The TEAEs with the highest incidence were gastrointestinal and nervous system events, but no serious adverse events occurred, and most TEAEs were mild in severity and transient in nature. There were also no clinically significant changes in electroencephalograms in subjects receiving LY2140023, and it was generally well tolerated in healthy subjects (Ayan-Oshodi et al, 2012). Furthermore, there was no evidence of withdrawal symptoms in subjects with the abrupt discontinuation of 4-week LY2140023 administration (Stauffer et al, 2014).…”

The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

“…Clinical trials for mGluR2/3 agonists showed neglectable spectrum of side effects commonly seen for antipsychotics targeting dopaminergic system. LY2140023, for instance, was generally well tolerated, produced no changes in electroencephalogram and did not increase the treatment-emergent adverse events (TEAEs) [113]. Moreover, there were no withdrawal effects after 4-week drug administration [114].…”