A BIOAVAILABILITY/BIOEQUIVALENCE AND PHARMACOKINETIC STUDY OF TWO ORAL DOSES OF TORASEMIDE (5 AND 10 mg): PROLONGED‐RELEASE VERSUS THE CONVENTIONAL FORMULATION

Abstract

1. The main objective of the present study was to compare the bioavailability/bioequivalence of a new prolonged-release (PR) formulation of torasemide with an immediate-release (IR) formulation. In addition, we assessed the pharmacokinetics of both formulations, as well as the urine pharmacodynamics. 2. Two doses (5 and 10 mg) of PR torasemide were compared with the same doses of IR torasemide in a single-blind, single-dose, two-treatment, two-period, cross-over, sequence-randomized clinical trial in 20 healthy volunteers (two groups; n = 10 in each group). Torasemide plasma concentrations were measured by high-pressure liquid chromatography-electrospray ionization mass spectrometry. Torasemide urine concentrations, the diuretic effect of torasemide, urine electrolytes and urine density were also determined. 3. Plasma bioequivalence parameters, based on logged values, were as follows: (i) in the 5 mg group, the area under the plasma drug concentration-time curve from t = 0 to last measurable drug concentration at time t (AUC(0-t)) tablet ratio was 1.03 (90% confidence interval (CI) 0.91-1.17) and C(max) was 0.82 (90% CI: 0.68-0.98); and (ii) in the 10 mg group, the AUC(0-t) was 1.07 (90% CI 0.99-1.14) and C(max) was 0.68 (90% CI 0.60-0.78). The PR formulation showed a significantly prolonged t(max) compared with the IR formulation. The amount of torasemide recovered in the urine 24 h after administration was higher with the PR formulation for both doses. The natriuretic rate versus torasemide excretion rate for the PR and IR formulations were successfully regressed to a sigmoid E(max) model. Pharmacodynamic urine evaluations were similar with both formulations, although urine volume and urine electrolyte excretion were lower for the PR formulation in the first hour after administration. However, the PR formulation showed higher natriuretic efficiency. No significant adverse events were reported. 4. In conclusion, both formulations of torasemide showed similar systemic exposure (AUC). However, the PR formulation had a lower rate of absorption (lower C(max) and prolonged t(max)). The PR formulation had urinary excretion rates that were associated with a higher natriuretic efficiency and more constant diuresis.

Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action

“…One was abandoned and the other improved antihypertensive efficacy only modestly and failed to improve fluid or electrolyte excretion likely because it prolonged the time to reach peak serum concentration only slightly. [34][35][36]…”

TORAFIC study protocol: torasemide prolonged release versus furosemide in patients with chronic heart failure

“…In the study by López et al, mean serum concentrations of PICP at the end of the study were 111 µg/l in the torasemide-IR group and 133 µg/l in the furosemide group, with a punctual estimation of the size effect of 22 µg/l (95% CI: 7-37) [30]. Standard errors in both groups of 19 and 17 cases were 3 and 7 µg/l, respectively, with a punctual estimation of the standard error of 22 (95% CI: [18][19][20][21][22][23][24][25][26][27][28][29]. If a difference between treatment of 15 µg/l and a standard error of 29 (both values included in their 95% CIs) are considered as clinically relevant, the sample size required at the a = p < 0.05 (two-sided) and a power (1-b) of 80% is 59 patients per group (a total of 118).…”

“…In addition, torasemide-IR has a longer half-life and duration of action, and higher bioavailability compared with furosemide [23]. A new, recently developed torasemide prolonged-release (PR) formulation has shown lower peak plasma levels while maintaining equivalent AUC of plasmatic levels compared with the IR formulation [24][25][26]. Moreover, a recent randomized noninferiority trial demonstrated that both PR and IR torasemide formulations were well tolerated and showed similar efficacy, tolerability and safety profiles in a population of mild-to-moderate hypertensive patients [27].…”

The impact of torasemide on haemodynamic and neurohormonal stress, and cardiac remodelling in heart failure – TORNADO: a study protocol for a randomized controlled trial

“…It is postulated that, compared with furosemide, torasemide reduces readmissions due to heart failure [6]; moreover, there is a discussion of its possible beneficial effect on mortality [7]. Yet torasemide has been shown to have less inter- and intra-individual variation in bioavailability and longer action than furosemide [8]. Vargo et al reported that heart failure does not affect the rate of absorption of orally administered torasemide, in contrast with furosemide, for which absorption was delayed [9].…”

“…Torasemide also induces greater improvements in functional and social limitations. Some clinical studies showed improvement in New York Heart Association (NYHA) functional class and pulmonary haemodynamics, as well as reduced body weight, in patients who received torasemide [8, 11, 12]. In a study by Müller et al , torasemide decreased the number of mictions at 3, 6 and 12 h after diuretic intake, as well as the urgency to urinate [11].…”