A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog.
Fifteen Beagle dogs were used to describe the anti-aldosterone effect of spironolactone (0, 0.8, 2 and 8 mg/kg) in a hyperaldosteronism model. The magnitude of the aldosterone response observed in this model was very similar to the one described in a dog with congestive heart failure (CHF). Each dog was allocated to a treatment group according to a 5 x 5 Latin square crossover design for five periods with a washout period of 7 days between each period. A maximal possible effect (E(max)) model was employed to determine the basic pharmacodynamic parameters of spironolactone, measured by high-performance liquid chromatography, in antagonizing the renal effects of aldosterone. The change in urinary sodium/potassium ratio in response to a single dose of aldosterone was calculated. The inhibition of this response by oral spironolactone administration was assessed. Aldosterone alone decreased sodium excretion by approximately 35% and urinary potassium concentrations increased by 25%, whereas the urine volume decreased, as expected. The effect of aldosterone on the Na(+)/K(+) ratio was completely reversed (88% inhibition) at a dose of 2 mg spironolactone/kg, while at the dose of 0.8 mg/kg, partial reversal was seen (27.5% inhibition). Urine flow rate was not significantly modified by either aldosterone treatment or aldosterone with spironolactone. The dose of spironolactone required to inhibit the action of aldosterone by 50% (ED(50)) was estimated to be 1.08 +/- 0.28 mg/kg. The E(max) was a ratio of 1.089 +/- 0.085, close to the observed value in negative control group (1.00 +/- 0.18). The proposed spironolactone dose using this E(max) model was 2 mg/kg b.w. once daily for the management.
Guyonnet
J
J
CEVA Santé Animale, R&D, ZI La Ballastière, Libourne Cedex, France. jerome.guyonnet@ceva.com
Elliott
J
J
Kaltsatos
V
V
D000818:Animals; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy / Q000662:veterinary*; D006929:Hyperaldosteronism / Q000188:drug therapy / Q000662:veterinary; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013148:Spironolactone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone