Effect of Multiple-Dose Aprocitentan Administration on the Pharmacokinetics of Midazolam in Healthy Male Subjects.

BACKGROUND: Aprocitentan is an orally active dual endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on cytochrome P450 (CYP) 3A enzymes was investigated in this open-label, two-treatment single-sequence study. OBJECTIVES: The primary and main secondary objectives were to study the pharmacokinetics of midazolam in the absence and presence of aprocitentan and the safety and tolerability of combined administration, respectively. METHODS: Nineteen healthy male subjects received a single dose of 8 mg midazolam. Thereafter, they started aprocitentan treatment (loading dose of 150 mg followed by 50 mg once daily) and received another single dose of midazolam with aprocitentan at steady state. Pharmacokinetics and tolerability of midazolam and its metabolite 1-hydroxy midazolam were assessed over 24 h after each midazolam administration. RESULTS: At steady state, aprocitentan did not affect the area under the plasma concentration-time curve and maximum plasma concentration (Cmax) of midazolam and 1-hydroxy midazolam, with a geometric means ratio (GMR) of midazolam + aprocitentan/midazolam alone close to 1 and 90% confidence intervals (CI) between 0.88 and 1.23. For the Cmax of 1-hydroxy midazolam the GMR (90% CI) was 0.86 (0.70-1.05). Somnolence, a known side-effect of midazolam, was reported as the most frequent adverse event. There were no relevant differences in tolerability parameters between treatments. CONCLUSION: Aprocitentan does not alter the pharmacokinetics of midazolam to a clinically relevant extent and was well tolerated when administered concomitantly. Therefore, aprocitentan can be administered together with drugs that are substrates of CYP3A without dose adjustments.