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

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SUMMARY



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.



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.



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 (AUC0–t) tablet ratio was 1.03 (90% confidence interval (CI) 0.91–1.17) and Cmax was 0.82 (90% CI: 0.68–0.98); and (ii) in the 10 mg group, the AUC0–t was 1.07 (90% CI 0.99–1.14) and Cmax was 0.68 (90% CI 0.60–0.78). The PR formulation showed a significantly prolonged tmax 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 Emax 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.



In conclusion, both formulations of torasemide showed similar systemic exposure (AUC). However, the PR formulation had a lower rate of absorption (lower Cmax and prolonged tmax). The PR formulation had urinary excretion rates that were associated with a higher natriuretic efficiency and more constant diuresis.
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Keywords: absorption; bioavailability; controlled-release preparation; efficiency; healthy volunteers; pharmacokinetics; torasemide

Document Type: Research Article

Publication date: May 1, 2009

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