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

• Published in: Drug design, development and therapy Vol. 13; pp. 949 - 964
• Main Authors: Sidharta, Patricia, Melchior, Meggane, Kankam, Martin K., Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.03.2019; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Administration, Oral; Adolescent; Adult; Age factors; Aged; Aged, 80 and over; Analysis; aprocitentan; Blood pressure; Body weight; Body Weight - drug effects; Diabetes; Dosage; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug Tolerance; Drugs; EKG; Electrocardiography; Endothelin; Endothelin 1; endothelin receptor antagonist; Endothelin Receptor Antagonists - administration & dosage; Endothelin Receptor Antagonists - adverse effects; Endothelin Receptor Antagonists - blood; Endothelin Receptor Antagonists - pharmacokinetics; Exposure; Female; Females; First-in-human study; Geriatrics; Headache; Health care; Healthy Volunteers; Heart failure; Humans; Hypertension; Kidney diseases; Macitentan; Male; Males; Middle Aged; Older people; Original Research; Parameters; Peptides; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pilot Projects; Plasma levels; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Receptors, Endothelin - metabolism; Review boards; Safety; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Time; Young Adult; United States > US; aprocitentan; pharmacokinetics; endothelin; endothelin receptor antagonist; first-in-human study; pharmacodynamics
• DOI: 10.2147/DDDT.S199051
• ISSN: 1177-8881

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. 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. 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 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. Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.