PT  - JOURNAL ARTICLE
AU  - Anna Thorsø Larsen
AU  - Nina Sonne
AU  - Kim V. Andreassen
AU  - Morten A. Karsdal
AU  - Kim Henriksen
TI  - Dose Frequency Optimization of the Dual Amylin and Calcitonin Receptor Agonist KBP-088: Long-Lasting Improvement in Food Preference and Body Weight Loss
AID  - 10.1124/jpet.119.263400
DP  - 2020 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 269--278
VI  - 373
IP  - 2
4099  - http://jpet.aspetjournals.org/content/373/2/269.short
4100  - http://jpet.aspetjournals.org/content/373/2/269.full
SO  - J Pharmacol Exp Ther2020 May 01; 373
AB  - Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible.SIGNIFICANCE STATEMENT Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of obesity.