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.
OBJECTIVE
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.


CONCLUSIONS
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.
Drug Research Center (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.
Maria Rosa
MR
Ballester
Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Universitat Autònoma de Barcelona (UAB) Bellaterra, Spain.
Eulàlia
E
Roig
Drug Research Center (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.
Ignasi
I
Gich
Drug Research Center (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Montse
M
Puntes
Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain ; Scientific Area, Ferrer Internacional, SA, Spain.
Joaquín
J
Delgadillo
Scientific Area, Ferrer Internacional, SA, Spain.
Benjamín
B
Santos
Drug Research Center (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ; Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.
Rosa Maria
RM
Antonijoan
D000368:Aged; D000369:Aged, 80 and over; D002626:Chemistry, Pharmaceutical; D002908:Chronic Disease; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005665:Furosemide / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D013030:Spain; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D013997:Time Factors; D000077786:Torsemide; D016896:Treatment Outcome; D014554:Urination / Q000187:drug effects
D003692:Delayed-Action Preparations; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013449:Sulfonamides; D005665:Furosemide; D000077786:Torsemide
controlled-release preparation; efficiency; furosemide; heart failure; pharmacodynamics; torasemide