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

Sachiko Miyakawa,Noriyuki Namiki,Naoki Inui,Keiichi Odagiri,Hiroshi Watanabe,Shinya Uchida,Shimako Tanaka,Akio Hakamata,Takahiro Goto

doi:10.4236/pp.2013.47078

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 bosen-tan); 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 (AUC0-8) 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.

Highlights

Pulmonary arterial hypertension (PAH) is a progressive and proliferative disease of the small pulmonary vasculature
Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment
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

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a progressive and proliferative disease of the small pulmonary vasculature. PAH leads to a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance to provoke right ventricular dysfunction and, death. Since 1990, several PAH-specific drugs have been approved for the indication of this orphan disease and survival does seem to have improved in the modern era [4,5]. Sildenafil (a selective inhibitor of cyclic guanosine monophosphate) and bosentan (an antagonist of endothelin-A and -B receptors) are drugs used in the treatment of PAH. Sildenafil improves exercise capacity and reduces PAP [6]. Bosentan reduces PAP and improves exercise capacity as well as functional class in patients with PAH [7,8]

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