A new study reported that sildenafil may be better suited for patients with pulmonary arterial hypertension (PAH) when given in combination with ambrisentan instead of bosentan. The study, “Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil-Bosentan and Sildenafil-Ambrisentan Combination Therapies for Pulmonary Hypertension,” was published in the journal Clinical and Translational Science.
PAH is a life-threatening disease, characterized by high blood pressure in the vessels carrying blood to the lungs. PAH can cause shortness of breath, dizziness, and tiredness, and as it progresses, pulmonary arterial pressure and pulmonary vascular resistance increase, leading to right ventricular failure and, ultimately, death.
Sildenafil is used to improve the exercise capacity in PAH patients. Ambrisentan relaxes the muscles in the blood vessels and also improves exercise capacity (six-minute walk distance) in patients with PAH, while bosentan has a similar mechanism of action as it decreases pulmonary vascular resistance.
Keiichi Odagiri from the Hamamatsu University School of Medicine in Japan and colleagues found that patients’ plasma concentration of sildenafil was significantly lower if the drug was given in combination with bosentan when compared with ambrisentan.
According to the team, this might be because bosentan induces the expression of cytochrome P450 3A4, which interferes with sildenafil pharmacokinetics. In contrast, ambrisentan has no such effect, so when the seven PAH patients who were enrolled in the study, all taking sildenafil, were switched from bosentan to ambrisentan, their sildenafil plasma concentrations were considerably higher.
The researchers highlighted that the PAH patients in the cohort received bosentan at a dose of 62.5 mg. twice a day, instead of the typically recommended dose of 125 mg. twice a day. The Japanese doctors used this dose, as they explained in a news release, “because of concerns about dose-dependent hepatic toxicity, even though the pharmacokinetics of bosentan and its metabolites are broadly comparable in Japanese and Caucasian individuals.”
The team reported that exercise tolerance was significantly better during treatment with sildenafil in combination with ambrisentan than during treatment with sildenafil plus bosentan. The median distance achieved in the externally paced 10-meter shuttle walking test was higher during the four to five weeks of treatment with ambrisentan compared to bosentan (340 vs. 280 meters, respectively).
The corresponding median six-minute walking distances were not significantly different (503 vs. 454 meters, respectively). However, peak oxygen consumption and oxygen consumption at anaerobic thresholds were significantly greater during the periods of treatment with ambrisentan versus bosentan. In terms of safety, there were no concerns with either combination therapy regime.
The researchers said they did not use invasive hemodynamic measures to assess the response to treatment. “The long-term efficacy and safety of the combination of sildenafil with ambrisentan should be examined in large-scale prospective randomized studies,” they cautioned.
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