Monika Lamparska-Przybysz, Piotr Guzenda, Joanna Hucz-Kalitowska, Mateusz Mach, Michał Mroczkiewicz, Katarzyna Bazydło, Krzysztof Dubiel, Maciej Wieczorek
Background and aims:
Renal sodium-glucose co-transporter 2 (SGLT2) inhibition is a promising new approach in therapy of type 2 diabetes. Currently, there are several clinical trials ongoing, with almost ten SGLT2 inhibitors in Phase III CPL-200-075 is a novel, selective and potent SGLT2 inhibitor that induce urinary glucose excretion with better pharmacokinetics than most advanced in development other SGLT2 inhibitors. In this studies we focused on pharmacodynamics of CPL-200-075.
Materials and methods:
Drug potency was evaluated in intraperitoneal glucose tolerance test (IGTT) and in mouse streptozoocine-induced diabetic model. In IGTT C57BL/6 males fasted for 12 h were given single oral dose of compound or placebo followed by i.p. administration of glucose (1 g/kg). Blood glucose levels were measured in several time points up to 120 min post glucose bolus. Mice with streptozotocin induced diabetes were fasted 3 h before dosing and were given a single oral dose of compound or vehicle. Food was given again to animals 4 h post dose. Blood glucose levels were measured in several time points up to 24h. In both studies, glucose levels were measured in a sample of tail vein blood using standard glucometer. Pharmacokinetic study was performed in normal Wistar rats. Overnight fasted animals were given compound in single dose of 1 or 5 mg/kg. Blood samples were collected via tail vein and compound’s serum concentration of was analyzed by LC-MS/MS.
CPL-200-075 displayed very good pharmacokinetic parameters. In rats after administration of single oral dose, we observed Cmax reaching 1563 ng/ml and 4233 ng/ml for 1 and 5 mg/kg, respectively. In the higher dose we observed that Cmax was stable from 2 to 8h post dosing. In IGTT CPL-200-075 decreased blood glucose levels by almost 50% when given in dose 5 mg/kg. The compound lowered blood glucose in dose-depended manner by 40, 60 and 80% when administrated in doses 5, 20 and 50 mg/kg, respectively. In streptozoocine-induced animal model of diabetes CPL-200-075 reduced blood glucose by over 100 mg/dl with little shift in minimum peak when compared to other SLGT2 inhibitors that currently are in clinical development. The effect on blood glucose after refeeding of STZ animals was comparable with SLGT2 inhibitors in clinical development used as control. Beneficial effect was stable up to 24h after dosing as indicated by glucose levels below that for vehicle group.
Administration of CPL-200-075 results in a dose-depended decrease in blood glucose levels in healthy and diabetic animals. This new compound is characterized by good pharmacokinetics and lover risk of hypoglycaemia.