in pulmonary vascular resistance and an increase of 0.58 L/min/m2 (97.5% CI: 0.28 to 0.93 L/min/m2) in cardiac index compared to placebo.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with macitentan in all subsets of the paediatric population for PAH (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of macitentan and its active metabolite have mainly been documented in healthy subjects. Exposure to macitentan in patients with PAH was approximately 1.2-fold greater than in healthy subjects. The exposure to the active metabolite in patients, which is approximately 5-fold less potent than macitentan, was approximately 1.3-fold higher than in healthy subjects. The pharmacokinetics of macitentan in PAH patients were not influenced by the severity of the disease.
After repeated administration, the pharmacokinetics of macitentan are dose-proportional up to and including 30 mg.
Absorption
Maximum plasma concentrations of macitentan are achieved about 8 hours after administration. Thereafter, plasma concentrations of macitentan and its active metabolite decrease slowly, with an apparent elimination half-life of approximately 16 hours and 48 hours, respectively.
In healthy subjects, the exposure to macitentan and its active metabolite is unchanged in the presence of food and, therefore, macitentan may be taken with or without food.
Distribution
Macitentan and its active metabolite are highly bound to plasma proteins (> 99%), primarily to albumin and to a lesser extent to alpha1-acid glycoprotein. Macitentan and its active metabolite ACT-132577 are well distributed into tissues as indicated by an apparent volume of distribution (Vss/F) of approximately 50 L and 40 L for macitentan and ACT-132577, respectively.
Biotransformation
Macitentan has four primary metabolic pathways. Oxidative depropylation of the sulfamide yields a pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 system, mainly CYP3A4 (approximately 99%) with minor contributions of CYP2C8, CYP2C9 and CYP2C19. The active metabolite circulates in human plasma and may contribute to the pharmacological effect. Other metabolic pathways yield products without pharmacological activity. Several members of the CYP2C family, namely CYP2C8, CYP2C9 and CYP2C19, as well as CYP3A4, are involved in the formation of these metabolites.
Elimination
Macitentan is only excreted after extensive metabolism. The major excretion route is via urine, accounting for about 50% of the dose.
Special populations
There is no clinically relevant effect of age, sex or ethnic origin on the pharmacokinetics of macitentan and its active metabolite.
Renal impairment
Exposure to macitentan and its active metabolite was increased by 1.3- and 1.6-fold, respectively, in patients with severe renal impairment. This increase is not considered clinically relevant (see sections 4.2 and 4.4).
Hepatic impairment
Exposure to macitentan was decreased by 21%, 34%, and 6% and, for the active metabolite by 20%, 25%, and 25% in subjects with mild, moderate or severe hepatic impairment, respectively. This decrease is not considered clinically relevant (see sections 4.2 and 4.4).
5.3 Preclinical safety data
In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of corona |
