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

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

Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan;.
Department of Drug Evaluation and Informatics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan;.
Department of Pharmacy Practice and Science, School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan..

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.

Keywords

Drug-Drug Interaction; Pulmonary Arterial Hypertension; Sildenafil; Bosentan; Pharmacokinetics

Conflicts of Interest

The authors declare no conflicts of interest.

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