RT Journal Article
SR Electronic
T1 Assessment of the Potential for Veverimer Drug-Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2021-000366
DO 10.1124/dmd.121.000366
A1 Dawn Parsell
A1 Jun Shao
A1 Robert Guttendorf
A1 Vandana Mathur
A1 Elizabeth Li
A1 Yick Sen Wu
A1 Li Tsao
A1 Scott Tabakman
A1 Yuri Stasiv
A1 Angela Lee
A1 Kalpesh Biyani
A1 Gerrit Klaerner
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/05/08/dmd.121.000366.abstract
AB Veverimer is a polymer being developed as a potential treatment for metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiological concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs. Significance Statement Patients with chronic kidney disease, who are usually on many drugs, are vulnerable to drug-drug interactions (DDIs). The potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the gastrointestinal tract. Based on the findings from in vitro and human studies, we conclude that veverimer is unlikely to have clinically significant DDIs.