Key result
Coadministration of sildenafil with ambrisentan resulted in a significantly higher sildenafil area under the curve (396.8 vs 165.8 ng•h/mL, P=0.018) compared to coadministration with bosentan.
Why the study?
Does sildenafil coadministered with ambrisentan improve pharmacokinetics and functional capacity compared to sildenafil with bosentan in patients with pulmonary arterial hypertension?
Cohort
Does sildenafil coadministered with ambrisentan improve pharmacokinetics and functional capacity compared to sildenafil with bosentan in patients with pulmonary arterial hypertension?
Absolute Event Rate: 396.8% vs 165.8%
p-value: p=0.018
Coadministration of sildenafil with ambrisentan results in higher sildenafil exposure and improved functional capacity compared to coadministration with bosentan in patients with pulmonary arterial hypertension.
Reduced sildenafil exposure with bosentan coadministration may warrant caution in PAH; leaves open optimal dosing pending larger trials.
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.
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Hakamata et al. (2016) conducted a cohort in Pulmonary arterial hypertension. Sildenafil + Ambrisentan vs. Sildenafil + Bosentan was evaluated on Area under the plasma concentration-time curve of sildenafil (p=0.018). Coadministration of sildenafil with ambrisentan resulted in a significantly higher sildenafil area under the curve (396.8 vs 165.8 ng•h/mL, P=0.018) compared to coadministration with bosentan.
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