Chemical formula: C₁₆H₁₄Br₂N₆O₄S Molecular mass: 545.914 g/mol PubChem compound: 25099191
Endothelin (ET)-1, via its receptors (ETA and ETB), mediates a variety of effects such as vasoconstriction, fibrosis, cell proliferation, and inflammation and is upregulated in hypertension. Aprocitentan is a dual ERA that inhibits the binding of ET-1 to ETA and ETB receptors and hence the effects mediated by these receptors.
In a thorough QT study in healthy subjects, once-daily administration of 25 mg (maximum therapeutic dose) aprocitentan at steady state did not prolong the QTc interval as the upper limit of the 90% confidence interval of the mean change from baseline in placebo-corrected QTc was less than 10 ms.
At four times the maximum therapeutic dose (100 mg), the upper limit of the 90% confidence interval of the mean change from baseline in placebo-corrected QTc was 10.4 ms.
Maximum plasma concentration (Cmax) of aprocitentan was achieved between 4 and 5 h after administration of 25 mg. Concentrations in plasma increased in a dose-proportional manner following once daily administration of 5 mg, 25 mg, and 100 mg. The absolute bioavailability after oral administration is not known.
With once daily administration, steady-state conditions were reached by Day 8 and accumulation compared to Day 1 was approximately 3-fold.
When a capsule formulation (used in early clinical studies) was taken with a high-fat, high-calorie meal by healthy subjects, aprocitentan median time to Cmax (tmax) was reached approximately one hour earlier, with a Cmax approximately 1.7-fold that in the fasted condition. Total exposure expressed as AUC0-∞ was approximately 1.2-fold that observed in the fasted condition. Food effect has not been specifically studied for the film-coated tablet. In the pivotal Phase 3 study, aprocitentan film-coated tablets were administered irrespective of food intake. The absorption of aprocitentan is not expected to be affected by meals.
Aprocitentan had an apparent volume of distribution of approximately 20 L and was highly bound to plasma proteins (>99%). The blood-to-plasma ratio was 0.63.
Aprocitentan was almost exclusively detected unchanged in plasma. The main metabolic pathways of aprocitentan were N-glucosidation of the sulfamide moiety catalysed by the glucuronyl transferases UGT1A1 and UGT2B7, and hydrolysis of the sulfamide moiety to the corresponding aminopyrimidine. Hydrolysis was mostly non-enzymatic.
After administration of a radiolabelled dose of aprocitentan, approximately 52% of radioactive drug-related material was eliminated via urine and 25% via faeces. A total of 0.2% and 6.8% of the administered dose was recovered in urine and faeces as unchanged aprocitentan, respectively.
The apparent oral body clearance is 0.30 L/h. The terminal plasma half-life of aprocitentan is approximately 46 h.
There were no clinically relevant effects of age (18–84 years), sex, body weight, or race on the PK of aprocitentan.
Total exposure to aprocitentan (AUC) in patients with severe renal impairment (eGFR 15–29 mL/min) compared to healthy subjects was increased by an average of 40%. This increase is not considered clinically relevant. Aprocitentan binding to plasma proteins was not influenced by renal function.
Total exposure to aprocitentan (AUC) in patients with moderate hepatic impairment (Child-Pugh class B) compared to healthy subjects was increased by an average of 23%. This increase is not considered clinically relevant. Aprocitentan binding to plasma proteins was not influenced by hepatic function.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and phototoxicity.
Histological findings in repeated-dose toxicity studies (degenerative liver changes, nasal cavity findings, and testicular changes) were observed only at exposures sufficiently in excess of the maximum human exposure, indicating low relevance in clinical use.
Testicular tubular degeneration was observed after repeated dosing in rats and dogs with safety margins of 8 (20.6)- and 4.9 (16.6)-fold the total (free) exposure at the maximum recommended human dose, respectively. However, no effects were noted on fertility or spermatogenesis in male rats.
In female rats, minimally increased pre-implantation loss (lower number of corpora lutea, implantation sites, and live embryos) was observed at 11 (29)-fold the total (free) exposure at the maximum recommended human dose. No effects on mating behaviour and reproductive performance were noted.
Aprocitentan did not induce teratogenicity in studies with pregnant rats and rabbits with safety margins of 2 (6)- and 14 (3)-fold the total (free) exposure at the maximum recommended human dose, respectively. However, ERAs as a class have shown teratogenicity in rats and rabbits, where the observed malformations indicate serious effects on developmental processes early in pregnancy (neural crest cell migration). Since teratogenic potential of aprocitentan was investigated only at exposures slightly above the exposure at the maximum recommended human dose, it is not known which exposures may elicit adverse effects on embryo-foetal development.
In pre- and post-natal development studies, female rats treated from late pregnancy through lactation showed reduced pup survival and impairment of the reproductive capability of the offspring.
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