832-P: Coadministration of Metformin with GLY-200, a Clinical-Stage Nonabsorbed Drug for the Treatment of Type 2 Diabetes (T2D), Has No Significant Impact on the Oral Absorption of Metformin in the Rat

Background: GLY-200 is a non-absorbed polymer drug currently in Phase 2 clinical trials for the treatment of T2D. GLY-200 was designed to reversibly enhance the barrier properties of the intestinal mucus lining to non-invasively mimic gastric bypass and duodenal exclusion devices. In view of this mechanism of action, GLY-200 has the potential to interfere with the absorption of orally available drugs. As such, we investigated the effect of GLY-200 on the oral absorption of metformin, an antidiabetic agent commonly used in combination with other glucose-lowering medications. Methods: Metformin (100 mpk) was administered by oral gavage in saline to male Sprague Dawley rats (6-8 weeks old). GLY-200 (400 mpk) was dosed either simultaneously in the same gavage solution, or prior (1- or 3-hours) to the metformin dose. Blood samples were drawn at 0, 0.25, 0.5, 1, 2, 4, 7, 10, and 24 hours following the metformin dose, and a pharmacokinetic (PK) analysis was performed using a noncompartmental model (Phoenix WinNonlin v. 8.3). Results: GLY-200 altered the rate but did not meaningfully alter the extent of metformin absorption. The greatest effect was observed when the two drugs were dosed together (Cmax ↓34%; tmax ↑100%; AUC ↑11%). The observed changes may be a result of slowed GI transit with GLY-200 administration. Conclusions: The oral absorption and PK profile of metformin was not significantly altered when the drug was coadministered with GLY-200 or given 1- or 3-hours after a GLY-200 dose. These results suggest that GLY-200 could be used in combination with metformin, whose pharmacologic action is not dependent on Cmax.