A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide‐induced diuresis in the dog

Abstract

This is an open access article under the terms of the Creative Commons AttributionNonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Paulin, A., Schneider, M., Dron, F., Woehrl e, F. A pharmacokinetic/ pharmacodynamic model capturing the time course of torasemide-induced diuresis in the dog. J. vet. Pharmacol. Therap. 39, 547-559.A pharmacokinetic/pharmacodynamic modelling approach was used to determine a dosage regimen which maximizes diuretic efficiency of torasemide in dogs. Kinetic profiles of plasma concentration, torasemide excretion rate in urine (TERU) and diuresis were investigated in 10 dogs after single oral administrations at 3 dose levels, 0.2, 0.8 and 1.6 mg/kg, and an intravenous injection of 0.2 mg/kg. Endogenous regulation was evidenced by a proteresis loop between TERU and diuresis. To describe the diuresis-time profile, TERU served as input into a turnover model with inhibition of loss of response, extended by a moderator acting on both loss and production of response. Estimated maximum inhibition of loss of response, I max , was 0.984 showing that torasemide is an efficacious diuretic able to suppress almost total water reabsorption. A TERU 50, value producing half of I max , of 1.45 lg/kg/h was estimated from the model. Pharmacokinetic and pharmacodynamic parameters were used to simulate the torasemide dose-effect relationship after oral administration. Model predictions were in good agreement with diuresis measured in a validation study conducted in 10 dogs, which were administered oral doses of 0.15, 0.4, 0.75, 1.5 and 4.5 mg/kg for 5 days. Finally, oral dose associated with the highest daily diuretic efficiency was predicted to be 0.1 mg/kg.

Pharmacokinetic and pharmacodynamic properties of orally administered torsemide in healthy horses

“…Torsemide has less diuretic resistance and anti‐aldosterone effects in dogs . Although bioavailability could not be calculated in our study because of unavailability of a torsemide formulation for IV use, it was absorbed after PO administration in all horses, reaching plasma concentrations similar to those observed in previous studies in dogs, rabbits, rats and humans . Our results showed that after a single dose of 6 mg/kg, plasma torsemide concentration reached a median C max of 10.14 µg/mL and time to reach peak plasma concentration was approximately 3 hours.…”

“…Our results showed that after a single dose of 6 mg/kg, plasma torsemide concentration reached a median C max of 10.14 µg/mL and time to reach peak plasma concentration was approximately 3 hours. In humans, peak plasma concentrations are obtained approximately 1 hour after PO torsemide administration and in dogs, peak plasma concentrations were observed at 1.5 hours after drug administration . For the single PO torsemide dose of 6 mg/kg, plasma torsemide concentrations over time showed great variability, and could not be fitted to a compartmental model.…”

“…8 Although bioavailability could not be calculated in our study because of unavailability of a torsemide formulation for IV use, it was absorbed after PO administration in all horses, reaching plasma concentrations similar to those observed in previous studies in dogs, rabbits, rats and humans. 2,11,13,27,28 Our results showed that after a single dose of 6 mg/kg, plasma torsemide concentration reached a median C max of 10.14 mg/mL and time to reach peak plasma concentration was approximately 3 hours. In humans, peak plasma concentrations are obtained approximately 1 hour after PO torsemide administration 2 and in dogs, peak plasma concentrations were observed at 1.5 hours after drug administration.…”

“…However, in humans, simultaneous administration of food with torsemide led to a decrease in drug absorption as indicated by a decrease in C max and a delay in reaching peak plasma drug concentration with no influence on total drug bioavailability and diuretic effects . In our study, a single PO dose of torsemide resulted in an elimination half‐life 3 times longer than what was observed in humans and slightly shorter than what was observed after IV torsemide administration in dogs . The terminal elimination half‐life is influenced by drug clearance, but plasma drug decay also can be influenced by the tissue distribution rate.…”

“…Torsemide has been widely used in humans and dogs with CHF, and shown less diuretic resistance . Although torsemide is proven to be safe and effective with good PO absorption in humans, dogs, cats, and rats . pharmacokinetic and pharmacodynamic studies have not been reported in horses.…”