Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil‐Bosentan and Sildenafil‐Ambrisentan Combination Therapies for Pulmonary Hypertension

Abstract

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4–5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration–time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension

“…Hakamata et al compared seven total patients on combination therapy with sildenafil and bosentan to the same patients on sildenafil and ambrisentan in an open-label, crossover study. 9 There was no significant difference in 6MWD between comparing treatment with sildenafil and bosentan to sildenafil and ambrisentan, but they did find a significant improvement in an externally paced shuttle walking distance by a median of 35.0 meters (P ¼ 0.042) in favor of the sildenafil and ambrisentan treatment. In another study, 20 patients with PAH who were already taking bosentan and sildenafil were transitioned to macitentan and sildenafil.…”

“…Chronic administration of bosentan results in a 40%-60% decrease in overall sildenafil plasma concentrations. [7][8][9][10] The reduction in sildenafil plasma concentrations with concomitant bosentan administration is thought to be due to increased sildenafil metabolism. Bosentan is known to induce expression of cytochrome P450 3A4 (CYP3A4), and sildenafil is predominantly metabolized by CYP3A4.…”

“… 3 , 4 Bosentan and sildenafil have been commonly used as combination therapy; however, several pharmacokinetic studies have shown a significant drug–drug interaction between these two medications, causing reduced sildenafil drug concentrations. 7 – 10 Recent clinical trials failed to show an improvement in clinical outcomes in patients who received combination therapy with bosentan and sildenafil. 11 , 12 For patients already receiving the combination of bosentan and sildenafil, transitioning to alternative medications may be warranted to avoid this drug interaction and therefore improve efficacy of combination therapy.…”

Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment

“…In case series, change of treatment due to side effects or unsatisfactory clinical response from bosentan to ambrisentan [37] and sildenafil to tadalafil [38] seemed to be beneficial. In a case report with 7 subjects, sildenafilambrisentan treatment showed higher medication concentrations for sildenafil than combination of sildenafilbosentan and was associated with a higher 6-min walking distance [39] .…”

Advantages and limitations of initial combination therapy in pulmonary arterial hypertension patients in Russia

“…При наличии фармакокинетической информации о начальной комбинации амбризентана и силденафила (в том числе об отсутствии лекарственного взаимодействия, опосредованного цитохромом Р450 [27,28]) к настоящему времени имеются лишь единичные клинические упоминания о стартовой комбинированной терапии этими препаратами, причем результаты комбинации не приводятся отдельно [22]. В 2019 г. в ретроспективном исследовании R. Sulica и соавт.…”