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

Figures

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  Figure 1. (A) Cardiodynamic evaluation: relationship between aprocitentan plasma concentration and ΔΔQTcF with 90% CI. (B) Mean observed and predicted ΔΔQTcF (±90% CI) vs observed median decile plasma concentrations. (C) Mean predicted (shaded gray area) ΔΔQTcF (±90% CI) vs observed geometric mean Cmax plasma concentrations of 5, 25, and 100 mg aprocitentan. In the graphs, the 10 ms threshold of regulatory concern (for the upper bound of the CI around the mean effect on QTc) is indicated, as referred to in the ICH E14 guideline.

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  Figure 2. Arithmetic mean changes (±SD) in baseline-corrected body weight (kg) after once-daily administration of 5, 25, and 100 mg aprocitentan for 10 days in healthy (A) and elderly subjects (B) (n=6 for 25 mg and 100 mg elderly, and placebo subjects; n=7 for 5 and 100 mg subjects; n=2 for placebo elderly).

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  Figure 3. Arithmetic mean (±SD) plasma concentration vs time profiles of aprocitentan after administration of single doses of aprocitentan to healthy subjects (n=6 for each dose level) in the absence (A) or presence (B) of food (n=5).

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  Figure 4. Arithmetic mean (±SD) plasma concentration following the last dose administration on Day 10 (A) and mean trough plasma concentration–time profiles (B) of aprocitentan after once-daily administration of multiple doses of aprocitentan to healthy subjects and 100 mg of aprocitentan to healthy elderly subjects (n=6 for 5, 25, and 100 mg elderly; n=5 in the 100 mg group).

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  Figure 5. Arithmetic mean AUCτ (±SD) of ET-1 on Day 1 (A) and Day 10 (B) after administration of 5, 25, or 100 mg aprocitentan or placebo once daily for 10 days to healthy subjects (n=6 for 5 and 25 mg; n=5 for 100 mg and placebo). Abbreviations: AUCτ, area under the plasma concentration–time curve over a dosing interval; ET-1, endothelin-1.