Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under Long-Term Use in Patients with Pulmonary Arterial Hypertension

Abstract

Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosentan); phase B (bosentan administered 3 h before sildenafil); and phase C (administered concomitantly). Blood samples were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or area under the plasma concentration-time curve (AUC 0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p = 0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p = 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra-and inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs to maximize the sildenafil concentration.

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

“…Bosentan induces expression of cytochrome P450 3A4 (CYP3A4) in the liver and intestinal wall by activating the pregnane X receptor, and this induction of CYP3A4 is considered responsible for the DDI between bosentan and sildenafil. In previous reports, long‐term treatment with bosentan resulted in ∼50–60% reduction in sildenafil AUC . In contrast, ambrisentan has the advantage of having no clinically important DDI with sildenafil, because it is only a weak activator of the pregnane X receptor .…”

“…In previous reports, longterm treatment with bosentan resulted in ß50-60% reduction in sildenafil AUC. 11,12,14 In contrast, ambrisentan has the advantage of having no clinically important DDI with sildenafil, because it is only a weak activator of the pregnane X receptor. 23 Indeed, the sildenafil AUC was essentially unchanged (by < 2.5%) when administered with ambrisentan, as compared with sildenafil monotherapy.…”

“…A combination of a PDE‐5 inhibitor and an ERA is recommended for advanced PAH . Although sildenafil and bosentan are often administered in combination, it is recognized that bosentan decreases the plasma concentration of sildenafil in the long term . It was reported that combination therapy of bosentan with sildenafil did not show a beneficial effect on 6‐minute walking distance (6MWD) .…”

“…9 Although sildenafil and bosentan are often administered in combination, it is recognized that bosentan decreases the plasma concentration of sildenafil in the long term. [10][11][12] It was reported that combination therapy of bosentan with sildenafil did not show a beneficial effect on 6-minute walking distance (6MWD). 13 Furthermore, a recent prospective trial found that this combination did not prolong the time to first morbidity or death compared with sildenafil monotherapy.…”