SESSION TYPE: DVT/PE/Pulmonary Hypertension Posters I
PRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PM
PURPOSE: The endothelin receptor antagonist macitentan is currently under investigation for the treatment of pulmonary arterial hypertension. The aim of this study was to evaluate the pharmacokinetics (PK), safety, and tolerability of single-dose macitentan in subjects with severe renal function impairment (SRFI) (defined as creatinine clearance <30 mL min-1) compared with demographically matched healthy subjects.
METHODS: In this prospective, open-label, single-center, phase I study (AC-055-112), 8 subjects with SRFI and 8 healthy subjects received a single dose of macitentan 10 mg on Day 1 and were followed-up to Day 14. 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 renal 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: All 16 subjects completed the study and were included in all analyses. Plasma concentration-time profiles of macitentan were comparable across groups. Geometric mean ratios (90% CI) of AUC0-∞, Cmax, and t1/2 for macitentan were 1.24 (0.83, 1.85), 1.11 (0.80, 1.54), and 1.08 (0.91, 1.27), respectively, and for ACT-132577 were 1.58 (1.24, 2.01), 1.39 (1.07, 1.81), and 1.32 (1.11, 1.58), respectively. There was a 7.3-fold greater exposure (AUC0-∞) to the inactive metabolite in SRFI versus healthy subjects. Minor increases in unbound fraction metabolites were noted in SRFI versus healthy subjects. Macitentan was well tolerated in both groups with only 2 AEs being reported, both in healthy subjects. Besides a non-clinically relevant decrease in blood pressure, macitentan had no apparent effects on vital signs, clinical laboratory or ECG variables.
CONCLUSIONS: Although the upper 90% CI for some PK variables were outside the reference limit, this was not considered clinically relevant, and neither was the increase in exposure to the inactive metabolite in SRFI subjects. Macitentan was well tolerated.
CLINICAL IMPLICATIONS: No dose adjustment is required when macitentan is administered to patients with any degree of renal impairment.
DISCLOSURE: Patricia Sidharta: Shareholder: Actelion Pharmaceuticals Ltd, Employee: Actelion Pharmaceuticals Ltd
Nicolas Lindegger: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd
Ivan Ulč: Employee: Consults for 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 renally 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