Indications
Aprocitentan, when used alongside other antihypertensive treatments, is indicated for the reduction of blood pressure in adult patients who have not achieved adequate control with other therapeutic options. This targeted use is supported by clinical guidelines and research data, which emphasize the drug's utility in managing resistant hypertension.
Pharmacodynamics
Aprocitentan operates pharmacologically by antagonizing ETA and ETB receptors, which are implicated in the development of hypertension. In the PRECISION trial, aprocitentan showed a statistically significant advantage over placebo in reducing both sitting systolic and diastolic blood pressures, achieving an average reduction in sitting trough blood pressure approximately 4 mmHg greater than placebo. The majority of its effectiveness in lowering blood pressure is observed within the initial two weeks of therapy. However, there is a notable risk of fetal harm associated with the use of endothelin receptor antagonists like aprocitentan if administered during pregnancy. Consequently, it is critical to exclude pregnancy before commencing treatment and to employ effective contraception both during treatment and for one month after its cessation. Due to these risks, aprocitentan is only accessible through the Tryvio REMS, a restricted distribution program.
Absorption
The precise oral bioavailability of aprocitentan remains undetermined. Following the administration of a single oral dose of 25 mg, the drug reaches a mean maximum concentration (Cmax) of about 1.3 mcg/mL and an area under the concentration-time curve (AUC0-tau) of roughly 23 mcg.h/mL. The time to reach maximum plasma concentration (Tmax) is typically between 4 to 5 hours, indicating a moderately timed absorption profile.
Metabolism
Aprocitentan is predominantly metabolized through N-glucosidation mediated by the enzymes UGT1A1 and UGT2B7, alongside non-enzymatic hydrolysis pathways. These metabolic routes facilitate the biotransformation of aprocitentan, contributing to its pharmacokinetic and pharmacodynamic properties.
Mechanism of Action
Aprocitentan functions as a dual endothelin receptor antagonist, effectively inhibiting the binding of endothelin-1 (ET-1) to both ETA and ETB receptors. ET-1, the predominant isoform in the human cardiovascular system, is constitutively produced by vascular endothelial cells to maintain vascular tone and is also present in various other cell types such as vascular smooth muscle cells, cardiomyocytes, and epithelial cells in the lungs and kidneys. Through its interaction with ETA and ETB receptors on vascular smooth muscle and endothelial cells, ET-1 regulates blood pressure by inducing either vasoconstriction or vasodilation. Notably, ET-1 is a potent vasoconstrictor, primarily acting via the ETA receptor and, under pathological conditions, exacerbating vasoconstriction through the ETB receptor. Overexpression of ET-1 and its receptors is observed in numerous pathologies, including essential hypertension and pulmonary arterial hypertension. By antagonizing these receptors, Aprocitentan effectively reduces the hypertensive effects associated with ET-1 overexpression, such as endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and elevated aldosterone synthesis.
