Retrospective evaluation of a dose‐dependent effect of angiotensin‐converting enzyme inhibitors on long‐term outcome in dogs with cardiac disease

et al. 2022

Preprint

Self Cite

The renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Breakthrough: A First-In-Class Virtual Simulator for Dose Optimization of ACE Inhibitors in Translational Cardiovascular Medicine

Schneider

et al. 2022

Preprint

Self Cite

“…Later, Hamlin & Nakayama (1998) found a single dose of benazepril at 0.5 mg/kg suppressed ACE for < 12 hours (21). Lastly, a recent retrospective study in dogs with valvular heart disease suggested improved outcomes with q12h dosage (22).…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 16, 2022. ; https://doi.org/10.1101/2022.11.14.516497 doi: bioRxiv preprint suppression lasting < 12 hours (21), and a recent retrospective study in dogs with valvular heart disease suggested improved outcomes with q12h dosage (22).…”

Section: Introductionmentioning

confidence: 99%

Breakthrough: A First-In-Class Virtual Simulator for Dose Optimization of ACE Inhibitors in Veterinary Cardiology

Schneider

et al. 2022

Preprint

Self Cite

The human and canine renin-angiotensin-aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors inhibitors (ACEi) in this indication. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses > 0.25 mg/kg P.O, thereby providing a rationale for the European label dose of 0.25 mg/kg P.O q24h in dogs with cardiovascular diseases. However, most of these earlier studies on benazepril pharmacodynamics relied on measures of ACE activity - a sub-optimal endpoint to characterize the effect of benazepril on the RAAS. Nonlinear mixed-effects (NLME) modeling is an established framework for characterizing the effect of therapeutics on complex biological systems, such as the RAAS cascade. Importantly for therapeutic schedule optimization, one can use such a model to predict the outcomes of various hypothetical dosing schedules via simulation. The objectives of this study were (i) to expand on previous NLME modeling efforts of the dose-exposure-response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis {angiotensins I, II, III, IV, (1-7)} by using a quantitative systems pharmacology (QSP) modeling approach; and (ii) to develop a software implementation of the model capable of simulating clinical trials in benazepril in dogs bedside dose optimization. This study expands on previous modeling efforts to characterize the changes in RAAS pharmacodynamics in response to benazepril administration and showcase how QSP modeling can be used for efficient dose optimization of ACEis at the bedside. Our results suggest that 0.5 mg/kg PO q12h of benazepril produced the most robust reduction in AngII and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.

“…While previous studies have assessed the effect of various ACEI doses in canine heart disease, relatively few have compared ACEI dosages within the same study, and cross-study comparisons are inherently di cult. A recent retrospective study suggested that twice daily dosing of ACEI was associated with improved long-term outcome in dogs with naturally-occurring cardiovascular disease compared to once daily dosing [39], but these ndings have yet to be con rmed prospectively. Furthermore, while the classical pathway has been the historical focus of RAAS-mitigating drug therapy in both human and veterinary medicine, it is now well-recognized that the RAAS homeostatic mechanism also includes additional signaling pathways that balance the effects of the classical RAAS.…”

Section: Introductionmentioning

confidence: 99%

Dose-response of benazepril on biomarkers of the classical and alternative pathways of the renin-angiotensin-aldosterone system in dogs

Guillot

et al. 2022

Preprint

Self Cite

Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin-angiotensin-aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet. Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 hours post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (-38%, P = 0.004), Ang1-5 (-53%, P = 0.001), ACE-S (surrogate for ACE activity; -59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; -22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; +58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans.