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Clinical Trial
. 2021 Mar;109(3):746-753.
doi: 10.1002/cpt.2043. Epub 2020 Sep 29.

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

Pierre Gueneau de Mussy  1 , Patricia N Sidharta  2 , Gregoire Wuerzner  1 , Marc P Maillard  1 , Nicolas Guérard  2 , Marc Iglarz  3 , Bruno Flamion  4 , Jasper Dingemanse  2 , Michel Burnier  1
Affiliations
Clinical Trial

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

Pierre Gueneau de Mussy et al. Clin Pharmacol Ther. 2021 Mar.

Abstract

Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.

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Conflict of interest statement

M.B. has received the research grant and consultant fees from Actelion Pharmaceuticals Ltd. and Idorsia Pharmaceuticals Ltd. P.N.S. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. N.G. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. M.S.M. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. M.I. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. B.F. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. J.D. is an employee of Actelion Pharmaceuticals Ltd. and current employee of Idorsia Pharmaceuticals Ltd. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Placebo‐corrected changes (mean ± SE) from baseline to day 9 in body weight in healthy normotensive subjects on a high sodium diet after administration of 10 mg, 25 mg, and 50 mg aprocitentan.
Figure 2
Figure 2
Placebo‐corrected changes (mean ± SE) from baseline to day 9 in hemoglobin in healthy normotensive subjects on a high sodium diet after administration of 10 mg, 25 mg, and 50 mg aprocitentan.
Figure 3
Figure 3
Mean cumulative 10 h urinary volume excretion (mL; ± SE) on days 1 and 9 in healthy normotensive subjects on a high sodium diet after administration of 10 mg, 25 mg, and 50 mg aprocitentan.
Figure 4
Figure 4
Change between predose day 9 and predose day 1 (± SD) for aldosterone, copeptin, and plasma renin activity in healthy normotensive subjects on a high sodium diet after administration of 10 mg, 25 mg, and 50 mg aprocitentan.
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