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Drug design, development and therapy

Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in patients with chronic heart failure.


PMID 26273191

Abstract

Diuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics. Randomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10 mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24 hours. Ten patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096 ± 0.03 mmol/μg vs 0.015 ± 0.0007 mmol/μg; P < 0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR. In a study with a limited sample size, our results suggest that 10 mg of torasemide-PR is more natriuretically efficient than 40 mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics.