Modeling the Effect of Amlodipine on the Renin-Angiotensin-Aldosterone System in Cats

Although amlodipine is commonly employed as a first-line treatment for systemic hypertension in cats, its influence on the feline renin-angiotensin-aldosterone system (RAAS) has not been thoroughly characterized. In dogs, amlodipine monotherapy is not recommended due to concerns that this drug upregulates renin activity, which can have negative pathophysiologic consequences. Newer methods of comprehensive RAAS “fingerprinting” allow simultaneous quantification of many different RAAS peptides, including those of the “classical” pathway (including angiotensin II and aldosterone), but also the counterregulatory “alternative” pathway, which is thought to have beneficial effects on the cardiovascular system. Our research group recently completed a study to investigate the impact of amlodipine on the both the classical and alternative arms of the RAAS in healthy cats. In this study, amlodipine resulted in significant increases in markers of both cascades, suggesting nonspecific RAAS activation by the drug compared to placebo. Advanced pharmacokinetic and pharmacodynamic (PK/PD) modeling of these data provide a rich window into the exposure-response relationship of amlodipine on the RAAS in cats. Furthermore, these results present an opportunity to delineate circadian variations in RAAS within this species. This approach further provides insights on the optimal use and dose of amlodipine in cats, and establishes a foundational basis for subsequent investigation in cats with systemic hypertension. In this session, two presenters – a systems pharmacologist and a clinical cardiologist – will describe the science and the clinical relevance of this research, and how applying the concepts of PK/PD modeling can help optimize prescription practices on the clinic floor.