Absorption, Distribution, Metabolism, and Excretion of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Humans

Background: Aprocitentan is an orally active, dual endothelin receptor antagonist that may offer a new therapeutic option for the treatment of difficult-to-control hypertension. Objective: To investigate safety, tolerability, mass balance, absorption, distribution, metabolism, and excretion of aprocitentan. Methods: In this single-center, open-label study, a single oral dose of 25 mg containing 3.7 MBq of 14 C-radiolabeled aprocitentan was administered to 6 healthy male subjects. Metabolites were identified using mass spectrometry and, where possible, confirmed and quantified with reference compounds. Results: Aprocitentan was well tolerated and there were no clinically significant findings for any safety variable. The geometric mean cumulative recovery of radioactivity from urine and feces over 14 days was 77% of the administered radioactive dose, with 52.1% cumulative recovery from urine and 24.8% from feces. Concentrations of total radioactivity in whole blood were markedly lower compared to plasma. In plasma, 94.3% of total radioactivity was aprocitentan. In urine and feces, 5 and 2, respectively (in feces one being aprocitentan) main products were identified. Metabolism data of aprocitentan identified two main elimination pathways, glucosidation to M3 and hydrolysis to M1, representing approximately 25% and 32% of the radioactive dose, respectively. Conclusions: Based on these metabolism data, aprocitentan can be concomitantly administered without dose adjustment with drugs that are inhibitors or inducers of any metabolizing enzyme, specifically cytochrome P450 enzymes.