Premium
A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide‐induced diuresis in the dog
Author(s) -
Paulin A.,
Schneider M.,
Dron F.,
Woehrlé F.
Publication year - 2016
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12316
Subject(s) - diuresis , diuretic , pharmacodynamics , pharmacokinetics , chemistry , pharmacology , reabsorption , oral administration , medicine , endocrinology , kidney
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 μg/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.