Abstract
Objective
The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH).
Methods
A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17.
Results
On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ©max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval \( {\left( {{\text{AUC}}_{\tau } } \right)} \) by 62.6% (90% CI 56.8–67.7%). Sildenafil increased bosentan Cmax by 42.0% (90% CI 15.4–74.8%) and \( {\left( {{\text{AUC}}_{\tau } } \right)} \) by 49.8% (90% CI 28.7–74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity.
Conclusions
In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.
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References
Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351:1655–1665
Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436
Barst RJ, Rubin LJ, Long WA, et al. (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334:296–302
Simonneau G, Barst RJ, Galie N, et al. (2002) Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 165:800–804
Actelion Pharmaceuticals I (2005) Tracleer [bosentan] tablets. Last updated February 15, 2007, available at: http://www.tracleer.com/pdf/PI_4pg_TR2454_032707_FINAL.pdf?kw=tracleer. Accessed on August 21, 2007
Pfizer I (2005) Revatio (sildenafil citrate) tablets. Last updated July 2006, available at: http://www.pfizer.com/pfizer/download/uspi_revatio.pdf. Accessed on August 21, 2007
Corbin JD, Francis SH (1999) Cyclic GMP phosphodiesterase-5: Target of sildenafil. J Biol Chem 274:13729–13732
Tantini B, Manes A, Fiumana E, et al. (2005) Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 100:131–138
Channick RN, Simonneau G, Sitbon O, et al. (2001) Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 358:1119–1123
Rubin LJ, Badesch DB, Barst RJ, et al. (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896–903
Galie N, Ghofrani HA, Torbicki A, et al. (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157
Lee SH, Channick RN (2005) Endothelin antagonism in pulmonary arterial hypertension. Semin Respir Crit Care Med 26:402–408
Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J (2004) Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 24:1007–1010
Lunze K, Gilbert N, Mebus S, et al. (2006) First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Eur J Clin Invest 36[Suppl 3]:32–38
Minai OA, Arroliga AC (2006) Long-term results after addition of sildenafil in idiopathic pah patients on bosentan. South Med J 99:880–883
Mogollon MV, Lage E, Cabezon S, et al. (2006) Combination therapy with sildenafil and bosentan reverts severe pulmonary hypertension and allows heart transplantation: Case report. Transplant Proc 38:2522–2523
Hoeper MM, Dinh-Xuan AT (2004) Combination therapy for pulmonary arterial hypertension: Still more questions than answers. Eur Respir J 24:339–340
Dingemanse J, van Giersbergen PLM (2004) Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 43:1089–1115
Cheitlin MD, Hutter AM, Jr., Brindis RG, et al. (1999) Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and practice executive committee. Circulation 99:168–177
Krenzelok EP (2000) Sildenafil: Clinical toxicology profile. J Toxicol Clin Toxicol 38:645–651
Hyland R, Roe EG, Jones BC, Smith DA (2001) Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil. Br J Clin Pharmacol 51:239–248
Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR (2005) Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 60:107–112
Eerkes A, Addison T, Naidong W (2002) Simultaneous assay of sildenafil and desmethylsildenafil in human plasma using liquid chromatography-tandem mass spectrometry on silica column with aqueous-organic mobile phase. J Chromatogr B Anal Technol Biomed Life Sci 768:277–284
Dell D, Lausecker B, Hopfgartner G, van Giersbergen PLM, Dingemanse J (2002) Evolving bioanalytical methods for the cardiovascular drug bosentan. Chromatographia 55:S115–119
Weber C, Schmitt R, Birnboeck H, et al. (1999) Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J Clin Pharmacol 39:703–714
Bachmann K, Ghosh R (2001) The use of in vitro methods to predict in vivo pharmacokinetics and drug interactions. Curr Drug Metab 2:299–314
Treiber A, Schneiter R, Hausler S, Stieger B (2007) Bosentan is a substrate of human oatp1b1 and oatp1b3: Inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin a, rifampicin, and sildenafil. Drug Metab Dispos 35:1400–1407
Sastry BK, Narasimhan C, Reddy NK, Raju BS (2004) Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 43:1149–1153
Acknowledgements
The authors acknowledge that editorial assistance was provided by Mukund Nori, PhD, MBA, Envision Pharma, Inc. in the preparation of this manuscript and that funding was provided by Pfizer, Inc.
Conflict of interest statement
G. Burgess and L. Collings are employees of Pfizer Ltd. J. Dingemanse and H. Hoogkamer are employees of Actelion Pharmaceuticals Ltd. This study was supported by Pfizer Ltd and by Actelion Pharmaceuticals Ltd.
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Burgess, G., Hoogkamer, H., Collings, L. et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 64, 43–50 (2008). https://doi.org/10.1007/s00228-007-0408-z
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DOI: https://doi.org/10.1007/s00228-007-0408-z