Main Research Findings

Ambrisentan is a medication used to treat pulmonary arterial hypertension (PAH) and systemic sclerosis (SSc). It works by blocking the action of endothelin, a hormone that constricts blood vessels. This constriction can lead to high blood pressure in the lungs (PAH) and problems with blood flow to the fingers and toes (SSc). 11 Studies have shown that ambrisentan can improve symptoms of PAH and reduce the risk of disease progression. 11 Ambrisentan has also been shown to be effective in treating digital ulcers, a common complication of SSc. 9 In a study of 11 patients with SSc, ambrisentan was found to promote healing of existing digital ulcers and prevent the development of new ulcers. 9

Ambrisentan is well absorbed in the gastrointestinal tract and metabolized by the liver. 8 The drug is primarily metabolized by glucuronidation and undergoes cytochrome P450 (CYP)-mediated oxidation to a lesser extent. 8 It is important to note that ambrisentan can interact with other medications, such as rifampin and digoxin. 8 Co-administration of rifampicin with ambrisentan results in increased metabolism of ambrisentan, leading to lower blood levels of ambrisentan. 8 Similarly, co-administration of ambrisentan with digoxin can lead to increased blood levels of digoxin.

Ambrisentan has also shown promise in treating combined pulmonary fibrosis and emphysema (CPFE). 6 In a case report, a patient with CPFE and severe pulmonary hypertension showed significant improvement in clinical symptoms after treatment with ambrisentan. 6 The improvement was attributed to the vasodilator and anti-proliferative effects of ambrisentan, which may have helped to reduce pressure in the pulmonary arteries and prevent further damage to the lungs. 6 Ambrisentan is also effective in treating pulmonary arterial hypertension in children. 17 A study that developed a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) concluded that ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. 17 The study also found that the exposure-response profiles observed in pediatric and adult populations with PAH suggest appropriateness of body-weight-based dosing in the pediatric population with PAH. 17

Studies have also shown that ambrisentan can be effective in treating portopulmonary hypertension, a serious complication of liver disease. 3 In a case report, two patients with WHO-FC IV PoPH were successfully treated with a combination of ambrisentan and tadalafil. 3 This suggests that oral vasodilator therapy, using a combination of ambrisentan and tadalafil, may be a safe and effective treatment option for patients with severe and rapidly progressing PoPH. 3 Additionally, ambrisentan has been shown to have beneficial effects on diabetic erectile dysfunction. 12 In a study, ambrisentan was found to improve erectile function in rats with diabetes. 12 The study suggests that ambrisentan may have a potential role in the treatment of diabetic erectile dysfunction. 12

Ambrisentan has been shown to have protective effects against experimental renal ischemia-reperfusion injury, a condition that occurs when blood flow to the kidneys is interrupted and then restored. 1 In a study comparing ambrisentan with bosentan, a dual endothelin type A/B receptor antagonist, ambrisentan was found to be more effective in protecting against renal injury. 1 Additionally, a study examining the long-term effects of ambrisentan on pulmonary hemodynamics in patients with PAH found that ambrisentan provided sustained improvements in pulmonary hemodynamics and these changes correlated with improvements in exercise capacity. 7 Ambrisentan has also been found to have antifibrotic effects in a non-alcoholic steatohepatitis mouse model. 2 This study suggests that ambrisentan may have a role in treating liver fibrosis. 2

Egln1^Tie2Cre mice are the only mouse model that develops severe PAH and occlusive pulmonary vascular remodeling, making them a valuable model for preclinical testing of new PAH drugs. 16 A study testing the therapeutic effects of sildenafil, ambrisentan, and treprostinil on these mice found that all three drugs attenuated right ventricular systolic pressure and improved cardiac output. 16 However, these drugs only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling. 16 These data demonstrate that Egln1^Tie2Cre mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. 16

Benefits and Risks

Benefit Summary

Ambrisentan has been shown to be effective in treating pulmonary arterial hypertension (PAH), systemic sclerosis (SSc), and combined pulmonary fibrosis and emphysema (CPFE). It can improve symptoms, reduce the risk of disease progression, and help prevent the development of digital ulcers. It is also being investigated for the treatment of other conditions, such as diabetic erectile dysfunction and renal ischemia-reperfusion injury. 11 9 6 2 12 1

Risk Summary

Ambrisentan can cause side effects, such as headache, flushing, and liver enzyme elevation. 11 It can also interact with other medications, such as rifampicin and digoxin. 8 It is important to discuss all medications with your doctor to avoid potential drug interactions. 11 8

Comparison Between Studies

Similarities Between Studies

Multiple studies have found that ambrisentan can be effective in treating PAH, SSc, and CPFE. These studies often share the same goals, which is to evaluate the effectiveness and safety of ambrisentan in treating these conditions. 11 9 6 17

Differences Between Studies

Although the studies generally agree on the benefits of ambrisentan, they differ in their study designs, subject populations, and outcomes. For example, some studies are designed to evaluate the long-term effects of ambrisentan, while others are designed to evaluate the short-term effects. 7 Additionally, studies vary in their inclusion criteria, meaning that some studies may have included patients with different types of PAH, SSc, or CPFE. 11 9 6 17 These differences make it challenging to directly compare the results of the studies. 7

Consistency and Contradictions of Results

The results of the studies suggest that ambrisentan is effective in treating PAH, SSc, and CPFE. However, there is some inconsistency in the results, particularly with regard to the effectiveness of ambrisentan in treating SSc. 9 The inconsistent findings may be due to a number of factors, including the small sample sizes of some of the studies and the variation in the types of SSc included in the studies. 9 More research is needed to determine the true effectiveness of ambrisentan in treating SSc. 9

Considerations for Real-World Application

Ambrisentan can be a valuable treatment option for patients with PAH, SSc, and CPFE. However, it is important to discuss all treatment options with your doctor. 11 9 6 Ambrisentan may not be appropriate for all patients and it is important to weigh the potential benefits and risks before starting treatment. 11 9 6

Limitations of Current Research

While the research on ambrisentan is promising, there are still some limitations. For example, more research is needed to determine the long-term effects of ambrisentan and its safety in different patient populations. 7 17 Additional research is also needed to evaluate the effectiveness of ambrisentan in combination with other medications. 14

Future Research Directions

Future research on ambrisentan should focus on addressing the limitations of current research. This includes conducting large-scale, long-term studies to determine the true effectiveness and safety of ambrisentan in various patient populations. 7 17 More research is also needed to evaluate the effectiveness of ambrisentan in combination with other medications and its potential for treating other conditions, such as diabetic erectile dysfunction and renal ischemia-reperfusion injury. 14 12 1

Conclusion

Ambrisentan is a promising treatment option for PAH, SSc, and CPFE. It has shown significant benefits in reducing the severity of these conditions and improving symptoms. 11 9 6 However, more research is needed to determine the long-term effects of ambrisentan and its safety in different patient populations. 7 17 If you have any questions or concerns about ambrisentan, be sure to speak with your doctor. 11 9 6