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 spironolact...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Journal of Veterinary Internal Medicine |
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| Online Access: | https://doi.org/10.1111/jvim.17255 |
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| author | Elizabeth Manson Jessica L. Ward Maria Merodio Emilie Guillot Thomas Blondel Karin Allenspach Oliver Domenig Jonathan P. Mochel |
| author_facet | Elizabeth Manson Jessica L. Ward Maria Merodio Emilie Guillot Thomas Blondel Karin Allenspach Oliver Domenig Jonathan P. Mochel |
| author_sort | Elizabeth Manson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-72b00b20b3c24915b17d468e905a3bd1 |
| institution | Kabale University |
| issn | 0891-6640 1939-1676 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Journal of Veterinary Internal Medicine |
| spelling | doaj-art-72b00b20b3c24915b17d468e905a3bd12025-01-27T15:22:40ZengWileyJournal of Veterinary Internal Medicine0891-66401939-16762025-01-01391n/an/a10.1111/jvim.17255Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogsElizabeth Manson0Jessica L. Ward1Maria Merodio2Emilie Guillot3Thomas Blondel4Karin Allenspach5Oliver Domenig6Jonathan P. Mochel7Department of Veterinary Clinical Sciences, College of Veterinary Medicine Iowa State University Ames Iowa USADepartment of Veterinary Clinical Sciences, College of Veterinary Medicine Iowa State University Ames Iowa USADepartment of Veterinary Clinical Sciences, College of Veterinary Medicine Iowa State University Ames Iowa USACeva Santé Animale Companion Animal Franchise Libourne FranceCeva Santé Animale Pharma Research & Development Libourne FrancePrecision One Health Initiative, Department of Veterinary Pathology, SMART Pharmacology, College of Veterinary Medicine The University of Georgia Athens Georgia USAAttoquant Diagnostics Vienna AustriaPrecision One Health Initiative, Department of Veterinary Pathology, SMART Pharmacology, College of Veterinary Medicine The University of Georgia Athens Georgia USAAbstract 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.https://doi.org/10.1111/jvim.17255angiotensin‐converting enzyme inhibitorbenazeprilatcaninecanrenonemineralocorticoid receptor antagonistTMS |
| spellingShingle | Elizabeth Manson Jessica L. Ward Maria Merodio Emilie Guillot Thomas Blondel Karin Allenspach Oliver Domenig Jonathan P. Mochel Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs Journal of Veterinary Internal Medicine angiotensin‐converting enzyme inhibitor benazeprilat canine canrenone mineralocorticoid receptor antagonist TMS |
| title | Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs |
| title_full | Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs |
| title_fullStr | Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs |
| title_full_unstemmed | Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs |
| title_short | Dose‐exposure‐response of CARDALIS® (benazepril/spironolactone) on the classical and alternative arms of the renin‐angiotensin‐aldosterone system in healthy dogs |
| title_sort | dose exposure response of cardalis r benazepril spironolactone on the classical and alternative arms of the renin angiotensin aldosterone system in healthy dogs |
| topic | angiotensin‐converting enzyme inhibitor benazeprilat canine canrenone mineralocorticoid receptor antagonist TMS |
| url | https://doi.org/10.1111/jvim.17255 |
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