Abstract
Veverimer is a polymer being developed as a potential treatment of 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 physiologic 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.
Highlights
Metabolic acidosis is a serious complication of chronic kidney disease (CKD) and accelerates its progression (Wesson et al, 2020)
In in vitro binding experiments using a panel of 16 test drugs, none of the five test drugs that are positively charged across the physiological pH range of the GI tract bound to veverimer under any condition (Figure 3)
Human Drug-Drug Interaction Studies Human drug-drug interaction (DDI) studies were conducted with drugs that demonstrated the greatest potential for direct interaction with veverimer in vitro and those with susceptibility to gastric pH changes
Summary
Metabolic acidosis is a serious complication of chronic kidney disease (CKD) and accelerates its progression (Wesson et al, 2020). Patients with CKD generate metabolic acids, and have a reduced capacity to excrete acid through the kidneys (Alpern and Sakhaee, 1997; Scialla and Anderson, 2013; Goraya and Wesson, 2017). Within the GI tract, the polymer restores the ability to excrete acid from the body. This mechanism of action is fundamental to the effectiveness of veverimer in treating metabolic acidosis and is distinct from the mechanisms of other drugs, such as proton pump inhibitors (PPIs) and histamine H2-receptor antagonists, that affect gastric pH but do not have an effect on systemic acid-base balance. The effect of veverimer on a background of PPI use was a relevant question because these drugs affect gastric pH and are commonly used
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