Dose-exposure-response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin-angiotensin-aldosterone system in healthy dogs

Abstract

Background: Benazepril exhibits a dose-dependent effect on biomarkers of the circulating renin-angiotensin-aldosterone system (RAAS) in dogs. Hypothesis/Objectives: To characterize the dose-exposure-response relationship of a fixed-dose combination product including benazepril and spironolactone (CARDALIS®) on RAAS biomarkers in dogs. Animals: Eighteen purpose-bred healthy beagle dogs. Methods: Three groups of 6 dogs received different doses of CARDALIS® for 14 days following induction of RAAS activation by feeding a low-sodium diet: (a) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h (label dose); (b) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h; or (c) benazepril 0.5 mg/kg + spironolactone 4 mg/kg PO q12h. Blood samples were collected at baseline and serial time intervals after CARDALIS® dosing to measure serum RAAS biomarkers and plasma concentrations of active drug metabolites. Time-weighted averages for serum RAAS biomarkers after CARDALIS® dosing at steady state were compared between dosage groups using Wilcoxon rank-sum testing. Results: Compared to the label dose, the highest dose of CARDALIS® was associated with a 30% decrease in angiotensin II (P =.03), 94% increase in angiotensin 1-7 (P =.03), 71% decrease in surrogate activity of ACE (P =.002), and 116% increase in circulating aldosterone (P =.02). CARDALIS® was well-tolerated at all doses with no clinically relevant changes in renal values or serum electrolytes. Conclusions and Clinical Importance: The combined CARDALIS® product leads to dose-dependent alterations of RAAS metabolites. These results could help inform clinical trials in dogs with heart disease.