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% (ED50) 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.