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

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.

Keywords: aprocitentan; endothelin; endothelin receptor antagonist; first-in-human study; pharmacodynamics; pharmacokinetics.

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 C_max 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.

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).

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).

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).

Figure 5

Arithmetic mean AUC_τ (±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: AUC_τ, area under the plasma concentration–time curve over a dosing interval; ET-1, endothelin-1.