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

Pulmonary arterial hypertension (PAH) is a progressive and proliferative disease of the small pulmonary vasculature. It is characterized by vasoconstriction, thrombosis in situ, and vascular remodeling and leads to a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance to provoke right ventricular dysfunction and ultimately, death.

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 (two men; age, 37 - 66 years old) with combination therapy of sildenafil and bosentan. Enrolled participants were randomly allocated to either treatment pattern 1 or 2. Pattern 1 began with phase C (administered concomitantly) and phase S (sildenafil administered 3 h before bosentan) followed by phase C and phase B (bosentan administered 3 h before sildenafil), while pattern 2 started with phase C and phase B followed by phase C and phase S. And a preliminary study was undertook to confirm the potential drug-drug interaction of bosentan on the pharmacokinetics of sildenafil; then the inter- and intra-individual variability of the sildenafil concentration during concomitant administration with bosentan was evaluated; finally, how the timing of administration influenced the sildenafil concentration was investigated.

The results showed that 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.

In conclusion, differences in the timings of administration of sildenafil and bosentan did not influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs (concomitantly or separately) to maximize the sildenafil concentration. The short-term drug-drug interaction between these agents is limited to large intra-individual variability.

Article by Sachiko Miyakawa, et al, from Japan.

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