Aprocitentan

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Endothelin Receptor Antagonists

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

C - Cardiovascular system

QC - Cardiovascular system

Aprocitentan exerts its pharmacologic effects by antagonizing receptors, ET_A and ET_B, which play a role in the pathogenesis of hypertension. In the PRECISION trial, aprocitentan demonstrated superiority to placebo in reducing both sitting systolic and diastolic blood pressures, with a mean reduction in sitting trough blood pressure of approximately 4 mmHg greater than placebo. Most of the antihypertensive effect of aprocitentan occurs within the first two weeks of treatment. Based on data from animal reproduction studies with other endothelin receptor antagonists, aprocitentan can cause fetal harm when administered during pregnancy. Prior to initiating treatment with aprocitentan, pregnancy should be excluded and acceptable contraceptive methods employed. Patients should monitor for pregnancy monthly and use effective contraception during treatment and for one month after discontinuation. Because of the significant risk of embryo-fetal toxicity, aprocitentan is only available through a restricted program called the Tryvio REMS.

Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system. It is produced constitutively by vascular endothelial cells to maintain vascular tone and is found in a variety of other cells including vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, neurons, and epithelial cells in the lungs and kidneys. ET-1 acts on two receptors, ET_A and ET_B, located on vascular smooth muscle cells and endothelial cells which serve to regulate blood pressure by inducing vasoconstriction or vasodilation. ET-1 is an extremely potent vasoconstrictor that works primarily via interactions with the ET_A receptor and, under pathologic conditions, further induces vasoconstriction via interactions with ET_B2. The overexpression of both ET-1 and ET receptors has been shown in a variety of pathologies, including essential hypertension, pulmonary arterial hypertension, chronic kidney disease, and diabetes mellitus. Aprocitentan is a dual endothelin receptor antagonist that inhibits the binding of ET-1 to both ET_A and ET_B receptors. This inhibition mitigates the hypertensive effects of ET-1 overexpression, including endothelial dysfunction, vascular hypertrophy and remodeling, sympathetic activation, and increased aldosterone synthesis.