A randomised, double-blind, placebo-controlled, parallel-design trial of multiple doses of tolevamer in healthy male volunteers

Abstract number: 1134_03_348

Davidson D., Porzio A., Nealon P., Peppe J.

Background:  

Tolevamer potassium-sodium (tolevamer) is a novel, high molecular weight, non-antibiotic polymer developed to treat Clostridium difficile associated diarrhoea (CDAD). The current form has been modified from an earlier compound, tolevamer sodium, by the addition of potassium to prevent the anionic polymer from exacerbating hypokalemia by binding and excreting intestinal potassium in the stool. Tolevamer sodium was shown to resolve the symptoms of CDAD with similar efficacy as vancomycin in a large Phase 2 study. Tolevamer is currently in Phase 3 development.

Objective:  

To determine the safety and tolerability of liquid tolevamer given at four different dose levels (6.0 g, 9.0 g, 12.0 g, and 15.0 g) to healthy male volunteers.

Methods:  

A randomized, double-blind, placebo-controlled, parallel-design, multiple dose study consisting of a screening period, a 9 day treatment period and a 1 week follow-up period was conducted. For each dose group, 10 subjects were randomized: 8 to active drug, and 2 to matching placebo. Half the subjects in each dose group received a loading dose (single dose equivalent to a total daily dose) on Day 1, while the other half received their loading dose on Day 9. All subjects received tolevamer t.i.d. on Days 2 through 8. Subjects received a controlled diet averaging 6600 mg/day potassium.

Results:  

Tolevamer was well tolerated with all forty subjects completing the study. All adverse events were of mild intensity, transient and resolved without sequelae. No dose relationship was apparent. Those considered related to study treatment were gastrointestinal disorders. Flatulence was the most common event. No clinically relevant changes were found in safety laboratory values, vital signs, or physical examination. Analysis of 24-hour urine collections demonstrated that potassium balance was achieved with tolevamer with the exception of a small reduction in mean potassium excretion from baseline to endpoint in the 15.0 g/day dose group of approximately 10 mmol potassium/day. No dose response was evident in urinary potassium excretion, and serum potassium was not adversely affected in any dose group.

Conclusion:  

Oral treatment with a daily dose of up to 15.0 g tolevamer divided t.i.d. and as a loading dose was safe and well tolerated by healthy male volunteers.