SESSION TYPE: DVT/PE/Pulmonary Hypertension Posters I
PRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PM
PURPOSE: This open-label, single-center, phase I study (AC-055-110) investigated the pharmacokinetics (PK), safety, and tolerability of the endothelin receptor antagonist macitentan in subjects with hepatic impairment of varying severity versus healthy subjects.
METHODS: Subjects were divided into four groups (n=8), based on hepatic function (Child-Pugh Class): A) mild hepatic impairment; B) moderate hepatic impairment; C) severe hepatic impairment; and D) healthy subjects. All subjects received a single dose of macitentan 10 mg. Length of follow-up was 10 days for Group D and 21 days for Groups A-C. Plasma PK parameters of macitentan and its active (ACT-132577) and inactive (ACT-373898) metabolites were derived by non-compartmental analysis of the plasma concentration-time profiles. No effect of hepatic impairment on macitentan PK was concluded when 90% confidence intervals (CI) of geometric mean PK parameter ratios were within reference limits of 0.8-1.25. Safety and tolerability evaluations included adverse events (AEs), ECG, vital signs, and clinical laboratory tests.
RESULTS: 32 and 31 subjects were available for the safety and PK analyses, respectively. Plasma concentrations of macitentan and ACT-132577 were generally lower in subjects with hepatic impairment than in healthy subjects, while those of ACT-373898 were only lower in Group B. There was no correlation between severity of hepatic impairment and plasma concentrations of macitentan/metabolites. Geometric mean ratios of PK parameters comparing hepatically impaired and healthy subjects ranged from 0.52 to 1.16 and, generally, 90% CI were outside the reference limits. A total of 11 AEs occurred and, with the exception of mild or moderate back pain and headache, were reported by single subjects. One subject in Group A who had abnormal liver enzymes at baseline displayed a further increase in aminotransferases which was reported as an AE. Clinically relevant changes in ECG or vital signs were not found.
CONCLUSIONS: The difference in macitentan PK between healthy and hepatically impaired subjects is not considered clinically relevant. Macitentan was well tolerated with no new or unexpected safety findings reported.
CLINICAL IMPLICATIONS: No dose adjustment is required when administering macitentan to patients with mild, moderate, or severe hepatic impairment.
DISCLOSURE: Patricia Sidharta: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd
Nicolas Lindegger: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd
Paul van Giersbergen: Consultant fee, speaker bureau, advisory committee, etc.: PvG acts as a consultant for Actelion Pharmaceuticals Ltd
Jasper Dingemanse: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd
This study describes the clinical pharmacology of macitentan in hepatically impaired subjects. Macitentan is currently under investigation as a treatment for pulmonary arterial hypertension in a Phase 3 clinical trial. Macitentan is not yet an approved medication. Actelion Pharmaceuticals Ltd, Allschwil, Switzerland