Review article: tolevamer, a novel toxin‐binding polymer: overview of preclinical pharmacology and physicochemical properties

Summary Background Tolevamer is a novel toxin‐binding polymer that is currently being investigated in clinical trials for the treatment of patients who have Clostridium difficile‐associated diarrhoea. Aims To summarize the results of in vitro and in vivo preclinical studies of tolevamer. In contrast to antibiotics, tolevamer binds C. difficile toxins to interrupt toxin‐mediated intestinal inflammation and tissue damage, and does not demonstrate direct antimicrobial activity. Methods Pharmacokinetics/pharmacodynamics were studied in rats and dogs; efficacy was studied in a hamster model. Results Studies in rats and dogs indicate that tolevamer is essentially non‐absorbed from the gastrointestinal tract and show that drug interactions with commonly used therapies are unlikely. Pharmacologic studies indicate that tolevamer reduces disease severity and recurrence rates in the hamster model of C. difficile‐associated diarrhoea and blocks the enterotoxic effects of toxin A in rat ileum. The binding parameters calculated for the interaction of tolevamer with toxins A and B provide a reasonable physicochemical model that supports the potential clinical utility of tolevamer. Conclusions These preclinical results are consistent with the effectiveness and safety profile of tolevamer observed in clinical studies in patients with C. difficile‐associated diarrhoea.