Aprocitentan: The First Endothelin Receptor Antagonist for Resistant Hypertension

Background: Hypertension is a serious health problem, and resistant hypertension occurs when blood pressure (BP) is uncontrolled despite at least 3 optimal-dosed agents of different pharmacologic classes. Aprocitentan is a novel pharmacological agent approved in early 2024 for treatment of hypertension, in patients whom BP is not adequately controlled while on other antihypertensive medications. Mechanism of Action, Pharmacodynamics and Pharmacokinetics: Aprocitentan acts as a dual endothelin receptor antagonist, inhibiting both ETa and ETb. It is postulated that low-renin models and salt-sensitive models of hypertension, consistent with resistant hypertension, exhibit increased levels of plasma ET-1. Thus, inhibition of ET-1 at ETa receptors inhibits vasoconstriction effects. The oral bioavailability of aprocitentan is currently unknown. Maximum plasma concentrations reaching a Cmax is within 4–5 hours with an effective half-life of 41 hours. Plasma concentrations increase in a dose-proportional manner and reach steady state within 8 days. The volume of distribution is 20 L, highly protein bound, primarily to albumin, and undergoes both renal and hepatic metabolism via UGT1A1- and UGT2B7-mediated N-glycosylation and nonenzymatic hydrolysis. Clinical Trials: In a phase 3, multicenter-study in adult patients (N = 730) with systolic blood pressure ≥140 mm Hg with a run-in placebo and standard background BP therapy continued throughout the study, placebo or aprocitentan (12.5, 25 mg) were randomized at various stages. Aprocitentan 12.5 mg was superior to placebo in reducing sitting (sitting systolic blood pressure) at week 4, and a persistence of the BP-lowering effect was demonstrated (sitting systolic blood pressure was maintained and was statistically superior at week 40) when aprocitentan 25 mg were rerandomized to placebo. Therapeutic Advance: Aprocitentan is a novel endothelin receptor antagonist approved for the treatment of resistant hypertension. It is a welcome development in the arsenal to fight against resistant hypertension for those with difficulty to manage with conventionally available antihypertensive medications.