Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry

摘要

Introduction: Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039. Methods: Rat hippocampal slices (n = 5) were prepared and Org 306039 was applied over a concentration range of 0-1000 mu M. Male Sprague-Dawley rats, implanted with telemetry EEG recording electrodes received either vehicle (n = 4) or 100 mg/kg Org 306039 (n = 4) by oral gavage daily for 10 days. EEG was recorded continuously for 22 +/- 1 h post-dose each day. Post-dose behavior observations were conducted daily for 2 h. Body temperature was measured at 1 and 2 h post-dose. On Day 7, blood samples were drawn for pharmacokinetic analysis of Org 306039. Results: In hippocampal slice, Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from CA1 area, indicating seizure-genic potential. In telemetered rats, Org 306039 was associated with a decrease in body weight, a decrease in body temperature and the appearance of seizure-related behaviors and pre-seizure waveforms on EEG. One rat exhibited an overt seizure. Plasma concentrations of Org 306039 were similar among the 4 rats in the Org-treated group. Small group size made it difficult to determine a PK-PD relationship. Discussion: These results indicate that the in vitro and in vivo models complement each other in the characterization of the seizure potential of CNS-targeted compounds such as the 5-HT2c agonist Org 306039. (C) 2014 Elsevier Inc. All rights reserved.