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.

Keywords: Non Linear Mixed Effect Model (NLME); PK/PD; aldosterone; diuresis; loop-diuretic; modeling; natriuresis; urine.

Figure 1

Schematic illustration of the final pharmacokinetic/pharma model, linking urinary torasemide excretion to plasma torasemide concentrations and the two pharmacodynamic submodels for diuresis and natriuresis. The effect of torasemide on diuresis was modeled with a direct response (power model). The natriuresis was modeled with an indirect response model. A modulator inhibiting the formation rate of sodium in urine was included to model reversible resistance to Torasemide (negative feedback loop).

Figure 2

Torasemide plasma concentration-time (μg/L) curve after daily administration for 14 days at doses of 0.1, 0.2, 0.4, and 0.8 mg/kg (Study 1).

Figure 3

Torasemide plasma concentration-time curve (μg/L) after daily administration on day 1 and daily5 and 14 at doses of 0.1, 0.2, 0.3, and 0.4 mg/kg (Study 2).

Figure 4

Torasemide urine quantity-time curve (μg) after daily administration on day 1 and daily between days 2, 5 and 14 at doses of 0.1, 0.2, 0.3, and 0.4 mg/kg (Study 2).

Figure 5

Mean and SD urine volumes (mL) excreted over 24 h obtained after single or daily repeated oral administrations of 0.1, 0.2, 0.3, or 0.4 mg/kg/day of torasemide once a day or 1, 2, 5, or 8 mg/kg/day of furosemide (in 2 daily administrations) in dogs of study 2.

Figure 6

Mean urine volumes (mL) excreted over 24 h profiles obtained after daily repeated administrations of 0.1, 0.2, 0.3, or 0.4 mg/kg/day of torasemide or 1, 2, 5, or 8 mg/kg/day of furosemide (in 2 daily administrations) in dogs of study 2.

Figure 7

Mean and SD quantities of sodium (mEq/day) excreted over 24 h obtained after single or daily repeated oral administrations of 0.1, 0.2, 0.3, or 0.4 mg/kg/day of torasemide once a day or 1, 2, 5, or 8 mg/kg/day of furosemide (in 2 daily administrations) in dogs of study 2.

Figure 8

Mean daily natriuresis time-profiles (mEq/day) profiles obtained after daily repeated administrations of 0.1, 0.2, 0.3, or 0.4 mg/kg/day of torasemide or 1, 2, 5, or 8 mg/kg/day of furosemide (in 2 daily administrations) in dogs of study 2.

Figure 9

Mean serum aldosterone concentration (ng/L) time-profiles profiles obtained before and 2 h after daily repeated administrations of 0.1, 0.2, 0.3, or 0.4 mg/kg/day of torasemide in dogs of study 1.

Figure 10

Dose response relationship between diuresis (mL/day period) and doses of torasemide in dogs (mg/kg/day) as computer from the PK/PD model. The variability observed with real data is represented with error bars (Doses with high variability in effect plotted in red).