Source: European Medicines Agency (EU) Revision Year: 2011 Publisher: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom
Pharmacotherapeutic group: Other antihypertensives
ATC code: C02KX03
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.
Thelin is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB).
Two randomized, double-blind, multi-centre, placebo-controlled trials were conducted to demonstrate efficacy. STRIDE-1, which included 178 patients, compared 2 oral doses of Thelin (100 mg once daily and 300 mg once daily) with placebo during 12 weeks of treatment. The 18 week STRIDE-2 trial, conducted in 246 patients, included 4 treatment arms: placebo once daily, Thelin 50 mg once daily, Thelin 100 mg once daily, and open-label bosentan twice daily (efficacy-rater blinded, administered according to the approved package insert).
STRIDE-4 included 98 patients randomised to sitaxentan sodium 50 mg, 100 mg, and placebo once daily for 18 weeks. Efficacy endpoints included sub maximal exercise capacity, WHO functional class and Time to Clinical Worsening for all studies, and haemodynamics for STRIDE-1.
Patients had moderate to severe (NYHA/WHO functional class II-IV) PAH resulting from idiopathic pulmonary arterial hypertension (IPAH, also known as primary pulmonary hypertension), connective tissue disease (CTD), or congenital heart disease (CHD).
In these studies, the study medicine was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen, and vasodilators (eg, calcium channel blockers, ACE inhibitors). Patients with pre-existent hepatic disease and patients using nonconventional PAH treatments (eg, iloprost) were excluded.
This was assessed by measuring distance walked in 6 minutes (6-minute walk test) at 12 weeks for STRIDE-1 and 18 weeks for STRIDE-2 and STRIDE-4. In both STRIDE-1 and STRIDE-2 trials, treatment with Thelin resulted in a significant increase in exercise capacity. The placebo-corrected increases in walk distance in the whole cohort compared to baseline were 35 metres (p=0.006; ANCOVA) and 31 metres (p<0.05; ANCOVA), respectively. In STRIDE-4, a statistically non-significant placebo-corrected mean improvement of 24.3 metres (p=0.2078) was observed in the whole cohort. Among patients with PAH associated with CTD in STRIDE-1 and STRIDE-2, a statistically significant difference versus placebo was observed (37.73 metres, p<0.05).
These were assessed in STRIDE-1 for both functional class II and III patients. Compared with placebo treatment, Thelin resulted in statistically significant improvement in pulmonary vascular resistance (PVR) and cardiac index (CI) after 12 weeks of treatment (see below).
Treatment Comparison of Change from Baseline in PVR, and CI at Week 12 by Functional Class – STRIDE 1: Sitaxentan 100 mg Versus Placebo:
| Functional Class | Median Difference from Placebo (95% CI) | P-Value |
|---|---|---|
| PVR (dyne*sec/cm5) | ||
| II | -124 (-222.7, -17.8) | 0.032 |
| III | -241,2 (-364.6, -136.4) | <0.001 |
| CI (L/min/m²) | ||
| II | 0.5 (0.2, 0.8) | 0.003 |
| III | 0.3 (0.1, 0.5) | 0.015 |
Systemic vascular resistance (-276 dynes*sec/cm5 (16%)) was improved after 12 weeks of treatment. The reduction in mean pulmonary artery pressure of 3 mmHg (6%) was not statistically significant.
The effect of Thelin on the outcome of the disease is unknown.
A reduction in symptoms of PAH were observed with sitaxentan sodium 100 mg treatment. Improvements in functional class were observed across all studies (STRIDE-1, STRIDE-2 & STRIDE-4).
There are no randomised studies to demonstrate beneficial effects on survival of treatment with sitaxentan sodium. However, patients completing STRIDE-2 were eligible to enrol in open-label studies (STRIDE-2X and STRIDE-3). A total of 145 patients were treated with sitaxentan sodium 100 mg and their long term survival status was assessed for a minimum of 3 years. In this total population, Kaplan-Meier estimates of 1, 2 and 3 year survival were 96%, 85% and 78% respectively. These survival estimates were similar in the subgroup of patients with PAH associated with CTD for the Thelin treated group (98%, 78% and 67% respectively). The estimates may have been influenced by the initiation of new or additional PAH therapies, which occurred in 24% of patients at one year.
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 Thelin is between 70 and 100%. When administered with a high fat meal, the rate of absorption (Cmax) of Thelin 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. Thelin did not affect fertility in males and females. Thelin 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 Thelin 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.
Thelin 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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