title: Characterization of the 5-HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet-induced obesity.
abstract: The 5-HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28-day lorcaserin treatment in a diet-induced obesity (DIO) model using male, Sprague-Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1-2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle-treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7-day treatment period; plasma C min and C max were in the range 13-160 ng/mL (1 mg/kg b.i.d.) and 34-264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0-5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2 ; Department of Pharmacology & Toxicology, University of Toronto Toronto, Ontario, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Jill
authors.initials: J
authors.lastname: Desnoyer
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Annalise
authors.initials: A
authors.lastname: Van Niekerk
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Leo B
authors.initials: LB
authors.lastname: Silenieks
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Winnie
authors.initials: W
authors.lastname: Lau
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Sandy
authors.initials: S
authors.lastname: Thevarkunnel
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Julia
authors.initials: J
authors.lastname: Izhakova
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2.
authors.forename: Ines Am
authors.initials: IA
authors.lastname: DeLannoy
authors.affiliation: Section of Biopsychology, Clarke Division, Centre for Addiction and Mental Health 250 College St., Toronto, Ontario, Canada, M5T 1R8 ; Department of Psychiatry & Psychology, University of Toronto Toronto, Ontario, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.affiliation: Animal Health Laboratory, U. Guelph Guelph, Ontario, Canada.
authors.forename: Josepha
authors.initials: J
authors.lastname: DeLay
authors.affiliation: InterVivo Solutions Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2 ; CanCog Technologies Inc. 120 Carlton St., Toronto, Ontario, Canada, M5A 4K2 ; Department of Clinical Studies, University of Guelph Guelph, Ontario, Canada ; Department of Biomedical Physics, University of Western Ontario London, Ontario, Canada.
authors.forename: Howard
authors.initials: H
authors.lastname: Dobson
keywords: Biomarkers; echocardiography; efficacy; lorcaserin; obesity; safety; valvulopathy