Macitentan: entry-into-humans study with a new endothelin receptor antagonist

Area of Science:

• Pharmacology
• Clinical Pharmacology
• Drug Metabolism

Background:

• Endothelin receptor antagonists are crucial in managing pulmonary arterial hypertension.
• Understanding the pharmacokinetic and tolerability profile of novel agents like macitentan is essential for therapeutic development.

Purpose of the Study:

• To evaluate the pharmacokinetics, pharmacodynamics, and tolerability of escalating single doses of macitentan in healthy male subjects.
• To determine the maximum tolerated dose (MTD) of macitentan.

Main Methods:

• A double-blind, placebo-controlled, dose-escalation study involving seven groups of eight healthy male subjects.
• Administration of macitentan at doses ranging from 0.2 mg to 600 mg, with placebo controls.
• Non-compartmental analysis of plasma macitentan, endothelin-1, and total bile salt concentrations, alongside metabolite analysis.

Main Results:

• Macitentan exhibited slow absorption with a half-life of 17.5 hours at 300 mg, and less than dose-proportional pharmacokinetics.
• A pharmacologically active metabolite, ACT-132577, was identified with a longer half-life (65.6 hours).
• Macitentan dose-dependently increased endothelin-1 levels and was well tolerated up to 300 mg, with headache, nausea, and vomiting as dose-limiting adverse events.

Conclusions:

• The pharmacokinetic and tolerability profile of macitentan supports a once-daily dosing regimen.
• Macitentan demonstrates potential for further clinical investigation in relevant patient populations.