PT - JOURNAL ARTICLE AU - Gerrit Klaerner AU - Jun Shao AU - Kalpesh Biyani AU - Matthew Kade AU - Paul Kierstead AU - Randi Gbur AU - Scott Tabakman AU - Son Nguyen AU - Jerry Buysse TI - Mechanism of Action of Veverimer: A Novel, Orally Administered, Non-absorbed, Counterion-Free, Hydrochloric Acid Binder under Development for the Treatment of Metabolic Acidosis in Chronic Kidney Disease AID - 10.1124/jpet.120.000190 DP - 2020 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - JPET-AR-2020-000190 4099 - http://jpet.aspetjournals.org/content/early/2020/10/08/jpet.120.000190.short 4100 - http://jpet.aspetjournals.org/content/early/2020/10/08/jpet.120.000190.full AB - Current management of metabolic acidosis in patients with chronic kidney disease (CKD) relies on dietary intervention to reduce daily endogenous acid production or neutralization of retained acid with oral alkali (sodium bicarbonate, sodium citrate). Veverimer is being developed as a novel oral treatment for metabolic acidosis through removal of intestinal acid, resulting in an increase in serum bicarbonate. Veverimer is a free-amine polymer that combines high capacity and selectivity to bind and remove hydrochloric acid (HCl) from the gastrointestinal (GI) tract. In vitro studies demonstrated that veverimer had a binding capacity of 10.7 {plus minus} 0.4 mmol HCl per gram of polymer with significant binding capacity (> 5 mmol/g) across the range of pH values found in the human GI tract (1.5 to 7). Upon protonation, veverimer bound chloride with high specificity, but showed little or no binding of phosphate, citrate or taurocholate (< 1.5 mmol/g), all anions commonly found in the human GI tract. Administration of veverimer to rats with adenine-induced CKD and metabolic acidosis resulted in a significant increase in fecal chloride excretion and a dose-dependent increase in serum bicarbonate to within the normal range, compared to untreated controls. Absorption, distribution, metabolism and excretion studies in rats and dogs dosed with 14C-labeled veverimer showed that the polymer was not absorbed from the GI tract and was quantitatively eliminated in the feces. Acid removal by veverimer, an orally administered, non-absorbed polymer, may provide a potential new treatment for metabolic acidosis in patients with CKD. Significance Statement Metabolic acidosis is a complication of CKD as well as a cause of CKD progression. Veverimer is a high capacity, selective, non-absorbed, HCl-binding polymer being development as a treatment for metabolic acidosis. Veverimer binds and removes hydrochloric acid from the gastrointestinal tract, resulting in increased serum bicarbonate and the correction of metabolic acidosis. Veverimer is not an ion-exchange resin and does not deliver sodium or other counterions, so may be appropriate for CKD patients with and without sodium-sensitive comorbidities.