<p>Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects</p>

Abstract

Background: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. Subjects and methods: In this study, the single-and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. Results: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single-and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ET B receptor antagonism, significantly increased with doses $25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Conclusion: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

“…Bosentan [20] Ambrisentan [21] Macitentan [22] Sitaxsentan [23] Atrasentan [24] Clazosentan [17] Zibotentan [25] Aprocitentan [26] Approval Bosentan is a non-peptide pyrimidine derivative that acts as a competitive, specific antagonist for both ET A and ET B . It was the first ERA to be approved for the treatment of PAH in patients with a World Health Organization (WHO) functional class III-IV [33].…”

Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension

“…1A) is the active metabolite of macitentan, also a dual ET A /ET B ERA, which demonstrated long-term efficacy in pulmonary hypertension. Aprocitentan is a potent, orally active, dual ET A /ET B ERA with an ET A /ET B inhibitory potency ratio of 1:16, as determined by in vitro functional assays (Iglarz et al, 2008), and a long half-life (44 hours) in humans (Sidharta et al, 2018).…”

Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet

“…The pharmacokinetic profile of aprocitentan was dose-proportional with a half-life of ~ 44 hours. 21 The efficacy, safety, and tolerability of aprocitentan were then investigated as monotherapy in patients with essential hypertension in a multicenter phase II dose finding study (ClinicalTrials.gov identifier: NCT02603809). Aprocitentan (5-50 mg) decreased BP in a dose-dependent fashion with a maximal effect of 9.9 ± 2.5 mmHg on systolic BP at 25 mg. 22 Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, and an increase in estimated plasma volume, but no change in weight vs. placebo.…”