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

Figures

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  FIGURE 1. Schematic representation of experimental design and timeline of sampling. There are 4 sampling days: BAS1 (before experimental RAAS activation with low‐sodium diet), BAS2 (after 5 days of low‐sodium diet), DOS1 (after first dose of CARDALIS®), and DOS14 (after 14 days of dosing with CARDALIS®). Three groups (n = 6 dogs each) received different doses of CARDALIS®. Colored circles indicate purpose and timing of blood samples collected on each sampling day. RAAS, renin‐angiotensin‐aldosterone system.

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  FIGURE 2. Time‐course of benazeprilat (A), canrenone (C), and 7‐alpha‐thiomethylspironolactone (TMS; E) plasma concentrations in 18 healthy dogs after the final dose of CARDALIS® administered at 3 different doses for 14 days (n = 6 dogs in each dosage group). The yellow line indicates mean plasma concentration and gray lines indicate individual dog results at each timepoint. Corresponding box‐and‐whisker plots indicate 24‐hour area under the curve of benazeprilat (B), canrenone (D), and TMS (F) concentration (ng/mL for all metabolites). The horizontal line represents median, box represents quartiles, and whiskers represent range, with outliers (>1.5 × interquartile range below Q1 or above Q3) plotted as dots. CARDALIS® dosage groups: Label dose q24h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h); label dose q12h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h); and double label dose q12h (0.5 mg/kg benazepril + 4 mg/kg spironolactone PO q12h).

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  FIGURE 3. RAAS biomarker serum concentrations in 18 healthy dogs following CARDALIS® administration at 3 different doses for 14 days (n = 6 dogs in each dosage group). Spaghetti plots show 24‐hour time course of RAAS biomarkers, with yellow lines indicating mean serum biomarker concentration and gray lines indicating individual dog results. Box‐and‐whisker plots show 24‐hour time‐weighted average (TWA) for biomarker concentration. Units for time‐weighted averages of RAAS biomarkers are ng/mL; ratios are unitless. The horizontal line represents median, box represents quartiles, and whiskers represent range, with outliers plotted as dots. P‐values are shown for group comparisons of TWA. CARDALIS® dosage groups: Label dose q24h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h); label dose q12h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h); and double label dose q12h (0.5 mg/kg benazepril + 4 mg/kg spironolactone PO q12h). AA2 ratio, ratio of aldosterone to angiotensin II and measure of adrenal responsiveness to angiotensin II; ACE‐S, surrogate measure of angiotensin‐converting enzyme activity; Ang, angiotensin; PRA‐S, surrogate measure for plasma renin activity.

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  FIGURE 4. Mean values of 24‐hour time‐weighted averages of renin‐angiotensin‐aldosterone system biomarkers in 18 healthy dogs treated with 14 days of CARDALIS® at 1 of 3 doses in a parallel‐group design. Sizes of circles are proportional to media time‐weighted averages of each analyte as shown (units of time‐weighted averages are ng/mL). CARDALIS® dosage groups: Label dose q24h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h); label dose q12h (benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h); and double label dose q12h (0.5 mg/kg benazepril + 4 mg/kg spironolactone PO q12h). ACE, angiotensin converting enzyme; Aldo, aldosterone; Ang, angiotensin; AT1R, angiotensin type 1 receptor.