Population Pharmacokinetics and Pharmacodynamics Modeling of Torasemide and Furosemide After Oral Repeated Administration in Healthy Dogs

Abstract

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 (T max 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 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 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 modeled 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.

Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs

“…Previous studies have shown a half-life of 0.5-1 h after IV administration, whereas the half-life has been reported as 30 min in the major disposition phase and approximately 7 h in the slow elimination phase after PO administration in dogs (5,6,38). According to another PK/PD study in healthy beagle dogs, the half-life after PO administration in dogs is 3 h, which is similar to the results of the present study (39).…”

Pharmacokinetics and diuretic effect of furosemide after single intravenous, oral tablet, and newly developed oral disintegrating film administration in healthy beagle dogs

“…Previous studies have shown a half-life of 0.5–1 h after IV administration, whereas the half-life has been reported as 30 min in the major disposition phase and approximately 7 h in the slow elimination phase after PO administration in dogs [ 5 , 6 , 38 ]. According to another PK/PD study in healthy beagle dogs, the half-life after PO administration in dogs is 3 h, which is similar to the results of the present study [ 39 ].…”

Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: TheCARPODIEMstudy

“…Results were primarily driven by a lower number of instances of worsening CHF that required doses above the prespecified range in the torasemide group. As previously stated, the specific torasemide and furosemide doses employed in our study were based on the production of equivalent degrees of diuresis 3,16,17 and were in general agreement with a previous clinical trial 14 . The comparative effect of torasemide vs furosemide on survival time in humans is a subject of interest, with 1 study 10 in favor of torasemide and others 8,9,22,23 reporting a neutral effect.…”

“…For dogs <4 kg, randomized to furosemide, and receiving ≤2.5 mg/(kg d), the daily PO dose of furosemide was given as a single daily dose. The specific torasemide and furosemide doses employed in our study were based on the production of equivalent degrees of diuresis, 3,16,17 and were in general agreement with a previous clinical trial 14 . For dogs initially in class IIIa, as signs of CHF improved, veterinarians were instructed to attempt to decrease the dose of study medications into the lower dose range.…”