Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data.

BACKGROUND: Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. OBJECTIVES: This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. DESIGN: This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). METHODS: The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. RESULTS: We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. CONCLUSION: By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease.

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.

Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease.

BACKGROUND: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. METHODS: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. RESULTS: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). CONCLUSIONS: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. TRIAL REGISTRATION: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension.

Since decades, bosentan has been in use for the treatment of pulmonary arterial hypertension (PAH). However, chronic exposure to bosentan leads to the development of resistance, tolerance, and serious adverse effects that have restricted its usage in clinical practices. To surmount these limitations, some new bosentan derivatives have been synthesized and evaluated for their therapeutic efficacy in PAH. Molecular docking analyses of all the synthesized derivatives were carried out using the endothelin (ET) receptor. In addition, the inhibitory ability of synthesized derivatives was determined in in vitro assay employing an ET-1 human ELISA kit. Among the synthesized derivatives, three derivatives namely 17d, 16j, and 16h with higher docking scores and lower IC50 values were selected for determination of the magnitude of the binding force between the derivative and ET receptor using molecular dynamics (MD) simulations study. Further, these derivatives were subjected to in vivo studies using monocrotaline (MCT) induced PAH in rat model. Results of in vivo studies inferred that the derivatives exhibit impressive ability to reduce PAH. Besides, its protective role was also evidenced in hemodynamic and right ventricular hypertrophy analyses, histological analysis, cardiac biomarkers, hypoxia-inducible factor 1 alpha (HIF1α) levels, and biochemical studies. Furthermore, gene quantification by quantitative RT-PCR and Western blot analysis was also performed to examine its effect on the expression of key proteins in PAH. Notably, amongst three, derivative 16h exhibited the most encouraging results in molecular docking analysis, in vitro, in vivo, histopathological, biochemical, protein expression, and MD studies. Besides, derivative 16h also showed impressive pharmacokinetic features in ADMET analysis. In conclusion, derivative 16 h could act as a reliable ET receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management.

New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension: A Systematic Review and Meta-Analysis.

Hypertension is one of the most common disorders encountered, yet pharmacotherapy for resistant hypertension has limited effective options. Aprocitentan is postulated to be a novel antihypertensive. The main goal was to determine the effect of aprocitentan on blood pressure among patients with hypertension. A thorough search of 5 electronic databases, including PubMed Central, PubMed, EMBASE, Springer, and Google Scholar, was carried out. The study included eight articles. With doses exceeding 25 mg, plasma ET-1(endothelin-1) concentrations, which show ETB (Endothelin receptor type B) receptor antagonism, significantly rose. Aprocitentan significantly reduced systolic and diastolic blood pressure with both doses of 10mg and 25mg in patients with hypertension. Further research is warranted to evaluate the efficacy, safety, and long-term outcomes of aprocitentan and its synergistic effect with other antihypertensives.

Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium-glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non-diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non-DKDs.

Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan in subjects with moderate hepatic impairment.

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child-Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (Cmax) reached at 4.0 h. There was no difference in Cmax, indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86-1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7-99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required.Clinical Trial Registration ClinicalTrials.gov NCT04252495.

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.

BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. INTERPRETATION: In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40. FUNDING: Idorsia Pharmaceuticals and Janssen Biotech.

Treatment of nonarteritic anterior ischemic optic neuropathy with an endothelin antagonist: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy)-a multicentre randomised controlled trial protocol.

BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAAION) is a major cause of blindness in individuals over 50 years of age, with no available effective treatment. The oral dual endothelin receptor antagonist, bosentan, increases retinal optic nerve head blood flow in healthy humans and glaucoma patients. The objective of this trial is to assess the efficacy of bosentan administered at the acute stage in improving outcomes in NAAION patients. METHODS: ENDOTHELION (ENDOTHELin antagonist receptor in Ischemic Optic Neuropathy) is a phase III, interventional, prospective, multicentre, placebo-controlled randomised double-blind clinical trial. The primary outcome is change in the visual field mean deviation (MD) at 3 months (Humphrey 30-2 SITA standard programme). Secondary outcomes include MD and visual acuity changes up to 24 months, changes in peripapillary retinal nerve fibre and macular ganglion cell layer thickness in the affected eye, as measured by optical coherence tomography, rate of NAAION bilateralisation at 2 years, and quality-of-life. Patients over 50 years of age presenting with typical NAAION of recent onset (less than 21 days) are randomly assigned to either 125 mg oral bosentan or placebo, twice a day, during 8 weeks. Besides visits during the treatment phase, patients attend follow-up visits at 2, 3, 6, 12 and 24 months. The inclusion of patients began in August 2015 at five French University hospital ophthalmology departments and two specialised ophthalmology centres. It is planned to include 86 patients in this trial. To date we have included 72 patients and 49 have completed the full follow-up process. DISCUSSION: An endothelin receptor antagonist is a potential approach to improving the anatomical and functional prognosis of patients with NAAION. This multicentre double-blind randomised controlled trial is an opportunity to assess (1) the effect of bosentan on the structure and function of the optic nerve in NAAION, at 3 months, (2) the effect of bosentan on the bilateralisation rate at 24 months and (3) the tolerance profile of bosentan in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02377271 . Registered on March 3, 2015.

Comparative assessment of efficacy and safety of ambrisentan and bosentan in patients with pulmonary arterial hypertension: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.

Aprocitentan (a Dual Endothelin-Receptor Antagonist) for Treatment-Resistant Hypertension.

ABSTRACT: Treatment-resistant hypertension (TRH) is associated with increased cardiovascular risks and progression of chronic kidney disease. The pathophysiology of TRH is multifactorial, including overactivity of the renin-angiotensin-aldosterone system and sympathetic nervous system, endothelial dysfunction, and volume overload. Endothelin-1 is a vasoconstrictive peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, endothelial dysfunction, vascular hypertrophy and remodeling, and fibrosis. Endothelin-1 acts through 2 receptors, ETA and ETB. Activation of ETA receptors in vascular smooth muscle cells results in vasoconstriction, whereas ETB receptor activation results in vasoconstriction in the vascular smooth muscle cells and vasodilation through nitric oxide release in endothelial cells. Aprocitentan is novel, oral, dual endothelin-receptor antagonist that has demonstrated a more favorable tolerability and safety profile in early clinical trials compared with other endothelin-receptor antagonists studied. Phase 2 trial data support a significant reduction in blood pressure compared to placebo and similar blood pressure reduction compared to a moderately dosed angiotensin-converting enzyme inhibitor in patients with essential hypertension. An ongoing phase 3 randomized clinical trial is evaluating aprocitentan's efficacy and safety in patients with TRH receiving multiple antihypertensives. Additional research is needed to determine aprocitentan's role in therapy, but this agent may be a suitable treatment option for TRH.

Multiple-Dose Pharmacokinetics, Safety, and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Healthy Japanese and Caucasian Subjects.

Aprocitentan is an orally active dual endothelin receptor antagonist currently in development for treatment of difficult-to-control (resistant) hypertension. In phase 1 and 2 studies, aprocitentan has been characterized predominantly in Caucasian subjects. In this bridging, double-blind study, 20 healthy Japanese and Caucasian male and female subjects received 25 mg of aprocitentan or placebo once daily for 10 days and were monitored until 216 hours after the last dosing. The pharmacokinetics of aprocitentan were similar between ethnicities. At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half-life was 49.1 and 48.8 hours for Japanese and Caucasian subjects, respectively. The accumulation index was around 3 for both populations. Geometric means ratios for maximum plasma concentration and area under the plasma concentration-time curve during 1 dosing interval were around 1, with 90% confidence interval ranging from 0.87 to 1.30. Aprocitentan was safe and well tolerated in both groups. As no clinically relevant differences were found between Japanese and Caucasian subjects, it is unlikely that the pharmacokinetics of aprocitentan would differ significantly between Caucasian subjects and other ethnicities. Aprocitentan can therefore be administered at a dose level of up to 25 mg in any ethnicity without dose adjustment.

Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet.

Aprocitentan is a novel, oral, dual endothelin receptor antagonist (ERA) in development in difficult-to-control hypertension. As fluid retention and edema are concerns with ERAs, we investigated whether aprocitentan causes weight gain in healthy subjects on a high sodium diet and explored potential mechanisms if occurring. This double-blind, randomized, placebo-controlled, crossover study enrolled 28 subjects. Three doses of aprocitentan (10, 25, or 50 mg/day for 9 days) were compared with placebo. Increases in body weight were observed with aprocitentan (placebo-corrected mean weight gains [90% confidence interval]) of 0.43 [0.05-0.80], 0.77 [0.03-1.51], and 0.83 [0.33-1.32] kg at 10 mg, 25 mg, and 50 mg, respectively. Decreases in hemoglobin and uric acid were observed. Plasma volume increased at most by 5.5% without dose-response relationship. Urinary sodium excretion decreased at 10 mg and 25 mg but not at 50 mg. Therefore, aprocitentan produced moderate weight increases in healthy subjects on high sodium diet, without obvious sodium retention.

Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta-analysis of randomized controlled trials.

AIM: To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease. METHODS: Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random-effect model to calculate the mean difference or risk ratio with the 95% CI. RESULTS: Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference -0.48, 95% CI -0.64 to -0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference -0.58, 95% CI -1.00 to -0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference -0.47, 95% CI -0.57 to -0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose-response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events. CONCLUSIONS: Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).

New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction.

The diuretic effects achieved with sodium glucose co-transporter 2 inhibitors (SGLT2i) may offset fluid retaining effects of the endothelin receptor antagonist (ERA) atrasentan while effects on albuminuria and kidney protection of both drug classes may be complimentary due to distinct mechanisms of action. Here, post-hoc analysis of the SONAR trial, in patients with type 2 diabetes and chronic kidney disease, show that six-weeks treatment with combined SGLT2i/atrasentan versus atrasentan alone decreased body weight, a surrogate for fluid retention, and further decreased albuminuria. Thus, these promising findings support future clinical studies to characterize the long-term efficacy and safety of combined SGLT2i/ERA treatment.

Safety of macitentan in sarcoidosis-associated pulmonary hypertension: a case-series.

BACKGROUND: Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population. OBJECTIVE: We investigated the safety and effect of macitentan as treatment for SAPH. METHODS: We retrospectively reviewed our patient database for all SAPH patients receiving macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected. RESULTS: Six cases (three men) with a median age of 64 years (range 52-74 years) were identified. During macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy. CONCLUSION: Macitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78).

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin.

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension.

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.

Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition.

Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by CHST3 and CHST13. In this study, we investigated whether dual ER inhibition in the liver could alter CHST3 and CHST13 expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased CHST3 and CHST13 expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased CHST3 and CHST13 expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that CHST3- and CHST13-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury.