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Aprocitentan: A new development of resistant hypertension.

ABSTRACT: As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT-132577), deriving its active form as a metabolite of macitentan, demonstrates oral potency as a dual endothelin (ET) receptor antagonist. This compound effectively obstructs the binding of endothelin-1 (ET-1) to both ETA and ETB receptors, exhibiting an inhibitory potency ratio of 1:16. Clinical investigation of aprocitentan has advanced to phase 3 trials, yielding promising preliminary outcomes.

SUBMITTER: Yao Y

PROVIDER: S-EPMC10339369 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Aprocitentan: A new development of resistant hypertension.

Yao Yao Y Fan Bin B Yang Bin B Jia Zixuan Z Li Bao B

Journal of clinical hypertension (Greenwich, Conn.) 20230619 7

As the blood pressure threshold for commencing antihypertensive treatment diminishes, the cohort suffering from resistant hypertension (RH) correspondingly expands. Notwithstanding the availability of known antihypertensive medications, there exists a conspicuous lacuna in therapeutic options specifically intended for the management of RH. Currently, aprocitentan is the sole endothelin receptor antagonist (ERA) under development for addressing this pressing clinical challenge. Aprocitentan (ACT- ...[more]

PMID: 37334561

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Project description: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.

Project description:BackgroundHypertension is one of the most prevalent disorders encountered in medical practice, yet effective pharmacotherapy options for resistant hypertension are limited. In this meta-analysis, we aimed to evaluate the efficacy and safety of aprocitentan in treating hypertension.MethodsWe searched PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library databases from inception to June 3, 2024, for randomized controlled trials (RCTs) that compared the efficacy and safety between aprocitentan and placebo in treating hypertension. According to the dosage of aprocitentan, the study was divided into a low-dose group (10-12.5 mg), medium-dose group (25 mg), and high-dose group (50 mg).ResultsThis meta-analysis included five RCTs, which incorporated 1224 patients, and displayed that aprocitentan can reduce the mean sitting systolic blood pressure (msSBP) [(low dose subgroup: mean difference (MD): -3.85 mmHg; 95% confidence interval (CI): -7.47 to -0.23; p = 0.040; medium dose group: MD: -5.56 mmHg; 95% CI: -10.69 to -0.44; p = 0.030)], mean sitting diastolic blood pressure (msDBP) (low dose subgroup: MD: -3.95 mmHg; 95% CI: -4.06 to -3.85; p < 0.001; medium dose group: MD: -4.75 mmHg; 95% CI: -5.91 to -3.60; p < 0.001), 24-hour ambulatory systolic blood pressure (maSBP) (low dose group: MD: -4.18 mmHg; 95% CI: -4.32 to -4.04; p < 0.001; medium dose group: MD: -5.89 mmHg; 95% CI: -6.03 to -5.75; p < 0.001), and 24-hour ambulatory diastolic blood pressure (maDBP) (low dose group: MD: -4.33 mmHg; 95% CI: -4.42 to -4.24; p < 0.001; medium dose group: MD: -5.82 mmHg; 95% CI: -5.91 to -5.73; p < 0.001). In the high-dose group, there was no difference between the aprocitentan and placebo groups in the msSBP (MD: -4.83 mmHg; 95% CI: -11.44 to 1.79; p = 0.150). Meanwhile, the safety profile of aprocitentan was good, and no significant differences in the frequency of adverse events (AEs) and serious adverse events (SAEs) were observed compared to the placebo.ConclusionsAprocitentan significantly reduces blood pressure and has a good safety profile. However, it is worth noting that high doses of aprocitentan (50 mg) did not yield better blood pressure-lowering effects.

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Aprocitentan: A new development of resistant hypertension.

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Aprocitentan: A new development of resistant hypertension.

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