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

Maria Rosa Ballester, Eulàlia Roig, Ignasi Gich, Montse Puntes, Joaquín Delgadillo, Benjamín Santos, Rosa Maria Antonijoan, Maria Rosa Ballester, Eulàlia Roig, Ignasi Gich, Montse Puntes, Joaquín Delgadillo, Benjamín Santos, Rosa Maria Antonijoan

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01549158.

Keywords: controlled-release preparation; efficiency; furosemide; heart failure; pharmacodynamics; torasemide.

Figures

Figure 1
Figure 1
Study schedule. Notes: The study consisted of three periods separated with a 7-day washout. The first and second period were crossover between torasemide PR and furosemide-IR whereas in the third period the patients taken Torasemide-IR. Abbreviations: h, hours; PR, prolonged release; IR, immediate release.
Figure 2
Figure 2
Mean urine excretion rate (μg/h) vs middle point (hours) of 10 mg torasemide-IR (Δ), 10 mg torasemide-PR (○), and 40 mg furosemide-IR (•). Notes: Data points are presented as the mean of the time-course of each drug excretion rate in urine. The first collected interval starts at 0 hours, after the ingestion of the drugs. Abbreviations: IR, immediate release; PR, prolonged release.
Figure 3
Figure 3
Mean natriuresis efficiency (mmol/μg) following oral administration of 10 mg torasemide-IR (Δ), 10 mg torasemide-PR (○), and 40 mg furosemide-IR (•) plotted against the midpoint (hours) of the entire collection interval. Notes: Data points are time-course (expressed as midpoint of the entire collected interval) of the mean natriuresis efficiency, calculated as the ratio between drug-induced natriuresis and drug recovered in urine over 24 hours. Abbreviations: IR, immediate release; PR, prolonged release.
Figure 4
Figure 4
Mean plasma concentration–time curves (ng/mL–hours) of 10 mg torasemide-IR (Δ), 10 mg torasemide-PR (○), and 40 mg furosemide-IR (•). Abbreviations: IR, immediate release; PR, prolonged release; Cp, plasma concentrations.
Figure 5
Figure 5
Mean urine volume excreted (mL) after 10 mg torasemide-IR (Δ), 10 mg torasemide-PR (○), and 40 mg furosemide-IR (•) plotted against the midpoint (hours) of the entire collection interval. Notes: The entire collection interval comprise 10 different intervals after the drug ingestion from 0 h to 24 h. Abbreviations: IR, immediate release; PR, prolonged release.

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