Key result
Torasemide produced similar diuresis and natriuresis to furosemide at 1/10 to 1/20 the dose, with a computed dose of 0.26 mg/kg/day selected to achieve a target diuresis of 460 mL/dog/day.
Why the study?
Torasemide is licensed in dogs for cardiogenic pulmonary oedema, but preclinical data were needed to define an optimally effective dosage regimen.
RCT (n=17)
Randomized crossover
No
Torasemide demonstrates linear pharmacokinetics and effective diuresis in healthy dogs, establishing a dose of 0.26 mg/kg/day for treating cardiogenic pulmonary edema.
May guide torasemide dosing in dogs with heart failure; leaves open clinical efficacy confirmation.
Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3-day washout and resumed daily treatment for 10 days (until Day-14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5-1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ±53mL/day for 10kg dogs) to 730 ±120mL after the first torasemide administration and up to 1150 ±252mL after ten administrations at the highest dose. At higher doses (≥ 0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day-1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modelled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ≥ 0.3 mg/kg, higher doses should be limited to 3-5 days to avoid supra-clinical effects in high responders.
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Pelligand et al. (2020) conducted an RCT in Healthy dogs (n=17). Torasemide vs. Furosemide (1 to 8 mg/kg/day) and Placebo was evaluated on Daily diuresis and natriuresis (PK/PD modeling). Torasemide produced similar diuresis and natriuresis to furosemide at 1/10 to 1/20 the dose, with a computed dose of 0.26 mg/kg/day selected to achieve a target diuresis of 460 mL/dog/day.
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