Chemical formula: C₁₈H₁₅ClN₂O₆S₂ Molecular mass: 454.905 g/mol PubChem compound: 216235
Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodelling and is pro-inflammatory. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), as well as other cardiovascular disorders and connective tissue diseases, including scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension, and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases. Additionally, PAH also is characterized by reduced nitric oxide activity.
ET-1 actions are mediated through endothelin A receptors (ETA), present on smooth muscle cells, and endothelin B receptors (ETB), present on endothelial cells. Predominant actions of ET-1 binding to ETA are vasoconstriction and vascular remodelling, while binding to ETB results in ET-1 clearance, and vasodilatory/antiproliferative effects due in part to nitric oxide and prostacyclin release.
Sitaxentan is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB).
Sitaxentan sodium is rapidly absorbed following oral administration. In PAH patients, peak plasma concentrations are generally achieved within 1-4 hours. The absolute bioavailability of sitaxentan is between 70 and 100%. When administered with a high fat meal, the rate of absorption (Cmax) of sitaxentan was decreased by 43% and the Tmax delayed (2-fold increase) compared to fasted conditions, but the extent of absorption was the same.
Sitaxentan sodium is more than 99% protein bound to plasma proteins, predominantly albumin. The degree of binding is independent of concentration in the clinically relevant range. Sitaxentan sodium does not penetrate into erythrocytes and does not appear to cross the blood-brain barrier.
Following oral administration to healthy volunteers, sitaxentan sodium is highly metabolised. The most common metabolic products are at least 10 times less potent as ETA antagonists than sitaxentan sodium in a standard in vitro test of activity. In vitro, sitaxentan sodium is metabolized by CYP2C9 and CYP3A4/5.
In vitro studies using human liver microsomes or primary hepatocytes show that sitaxentan sodium inhibits CYP2C9, and, to a lesser extent, CYP 2C8, CYP2C19 and CYP3A4/5.
Approximately 50-60% of an oral dose is excreted in the urine with the remainder eliminated in the faeces. Less than 1% of the dose is excreted as unchanged active ingredient. The terminal elimination half-life (t½) is 10 hours. Steady state in volunteers is reached within about 6 days.
No unexpected accumulation in the plasma was observed after multiple dosing at the recommended dose of 100 mg once daily. However, at doses of 300 mg or higher, non-linear pharmacokinetics result in disproportionately higher plasma concentrations of sitaxentan sodium.
Based on results of the population pharmacokinetic analysis and pooled pharmacokinetic data over several studies, it was found that gender, race, and age do not clinically significantly affect the pharmacokinetics of sitaxentan sodium.
The influence of liver impairment on the pharmacokinetics of sitaxentan sodium has not been evaluated. Refer to section 4.3.
In repeated-dose toxicity studies, dose-related liver changes (weight, centrilobular hypertrophy, occasionally necrosis), induction of hepatic drug metabolising enzymes and slightly decreased erythron parameters were seen in mice, rats and dogs. At high doses, dose-related increases in prothrombin time (PT) and activated partial thromboplastin time (APTT) were also seen, most prominently in rats, and coagulopathy (bleedings) in rats and dogs, but not mice. The significance of these findings for humans is unknown.
Testicular tubular atrophy was observed in rats, but not in mice or dogs. In the 26-week study, moderate to marked diffuse seminiferous tubular atrophy was present at a very low incidence, whereas in the 99-week study there was a dose-related, slightly increased incidence of minimal to mild focal atrophy at doses providing 29 to 94 times the human exposure.
Reproduction toxicity has been evaluated in rats only. Sitaxentan did not affect fertility in males and females. Sitaxentan was teratogenic at the lowest tested dose in rats, corresponding to exposures more than 30 times the human exposure. Dose-dependent malformations of the head, mouth, face and large blood vessels occurred. A NOAEL has not been established.
Administration of sitaxentan to female rats from late-pregnancy through lactation reduced pup survival, and caused testis tubular aplasia and delayed vaginal opening at the lowest exposure tested (17-45 times the human exposure). Large/abnormally shaped livers, a delay in auditory function development, a delay in preputial separation and a reduction in the number of embryonic implants occurred at higher maternal doses.
In vitro and in vivo tests on genetic toxicology did not provide any evidence for a clinically relevant genotoxic potential.
Sitaxentan was not carcinogenic when administered to rats for 97-99 weeks or when administered to p53(+/-) transgenic mice for 6 months.
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