title: A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide-induced diuresis in the dog.
abstract: 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, Imax, was 0.984 showing that torasemide is an efficacious diuretic able to suppress almost total water reabsorption. A TERU50,value producing half of Imax, 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.
authors.affiliation: Global Drug Development Division, Vétoquinol S.A., Lure, France. angelique.paulin@vetoquinol.com.
authors.forename: A
authors.initials: A
authors.lastname: Paulin
authors.affiliation: Global Drug Development Division, Vétoquinol S.A., Lure, France.
authors.forename: M
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Global Drug Development Division, Vétoquinol S.A., Lure, France.
authors.forename: F
authors.initials: F
authors.lastname: Dron
authors.affiliation: Global Drug Development Division, Vétoquinol S.A., Lure, France.
authors.forename: F
authors.initials: F
authors.lastname: Woehrlé
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs / Q000097:blood* / Q000652:urine; D005260:Female; D006207:Half-Life; D008297:Male; D008954:Models, Biological; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077786:Torsemide
chemical_list: D004232:Diuretics; D013449:Sulfonamides; D000077786:Torsemide