Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.
Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension
Angeli F.;
2021-01-01
Abstract
Aprocitentan (ACT-132577) is an orally active, dual endothelin-1 (ET-1) receptor antagonist that prevents the binding of ET-1 to both ETA/ETB receptors. It is an active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. Aprocitentan is highly bound to plasma proteins and is eliminated in both urine and feces. It is well tolerated across all doses (up to 600 mg with single dose and 100 mg once a day at multiple doses). Its pharmacokinetic profile shows a half-life of 44 h, fitting a once-daily dosing regimen with plasma ET-1 concentrations (reflecting ET receptor antagonism), significantly increasing with doses ≥ 25 mg. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, fed and fasted conditions, and renal function have been observed. Aprocitentan in patients with resistant hypertension is currently under investigation in the PRECISION phase III trial (ClinicalTrials identifier: NCT03541174). Nonetheless, results of pre-clinical data and studies in humans support the potential role of aprocitentan in this clinical setting. The absolute blood pressure (BP) reductions with aprocitentan are in the ranges established as a surrogate for reduction in cardiovascular morbidity in hypertension. Significant changes in BP with aprocitentan are observed within 14 days, and its BP-lowering effects have also been documented with ambulatory BP monitoring. Finally, aprocitentan enhances the BP-lowering effects of other antihypertensive drugs, including renin-angiotensin-system blockers. In conclusion, aprocitentan ameliorates the effects of ET-1 and could potentially reduce BP and provide broader cardiovascular protection in patients with resistant hypertension. Available data support the hypothesis that this new agent could expand our antihypertensive arsenal in resistant hypertension, making aprocitentan an attractive candidate for further large-scale trials.
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