Abstract
Tadalafil is a selective cyclic guanosine mono-phosphate-specific phosphodiesterase type 5 inhibitor that is effective in improving exercise ability, the time to clinical worsening and health-related quality of life (HR-QOL) scores in patients with pulmonary arterial hypertension (PAH).
In a large, 16-week, randomized, double-blind, placebo-controlled, multicentre, phase III trial (PHIRST) in patients aged ≥14 years with PAH (WHO group I), tadalafil 40 mg once daily (the recommended dosage) significantly increased the mean placebo-corrected 6-minute walk distance (6MWD) by 33 m from baseline (primary endpoint).
In treatment-naive patients, tadalafil 40 mg once daily significantly increased the mean placebo-corrected 6MWD by 44 m at week 16, whereas in patients receiving bosentan 125 mg twice daily as background therapy there was a mean change of 23 m, which was not significant.
Both the time to the first occurrence of clinical worsening and the incidence of clinical worsening were significantly reduced in recipients of tadalafil 40 mg once daily compared with recipients of placebo.
Furthermore, at week 16, tadalafil improved most HR-QOL outcomes from baseline to a significantly greater extent than placebo.
Preliminary data from an extension of the PHIRST trial suggest that the improvements in 6MWD are maintained for up to 1 year in recipients of tadalafil 20 or 40 mg once daily.
Treatment with tadalafil was generally well tolerated, with adverse events that were transient in nature and of mild to moderate intensity.
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References
Galié N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30(20): 2493–537
McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009 Apr 28; 119(16): 2250–94
National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK. Heart 2008; 94 Suppl. I: 1–41
Rubin LJ, Badesch DB. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med 2005 Aug 16; 143(4): 282–92
Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004 Oct 14; 351(16): 1655–65
Peacock AJ, Murphy NF, McMurray JJ, et al. An epide-miological study of pulmonary arterial hypertension. Eur Respir J 2007 Jul; 30(1): 104–9
Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006 May 1; 173(9): 1023–30
Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987 Aug; 107(2): 216–23
WHO. The global alliance against chronic respiratory diseases: pulmonary hypertension [online]. Available from URL: http://www.who.int/gard/news_events/3-15_Plumonary%20hyperthension-Dr%20M.%20Hmpert.pdf [Accessed 2009 Oct 20]
D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991 Sep 1; 115(5): 343–9
Hoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs 2005; 65(10): 1337–54
Hoeper MM, Markevych I, Spiekerkoetter E, et al. Goaloriented treatment and combination therapy for pulmonary arterial hypertension. Eur Resp J 2005; 26(5): 858–63
Xu W, Kaneko FT, Zheng S, et al. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 2004 Nov; 18(14): 1746–8
Reffelmann T, Kloner RA. Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation 2003 Jul 15; 108(2): 239–44
Montani D, Chaumais MC, Savale L, et al. Phosphodiesterase type 5 inhibitors in pulmonary arterial hypertension. Adv Ther 2009 Sep 19; 26(9): 813–25
Curran M, Keating G. Tadalafil. Drugs 2003; 63(20): 2203–12
Eli Lilly and Company. ADCIRCA (tadalafil) tablets for oral administration: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022332lbl.pdf [Accessed 2009 Oct 7]
Galié N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009 Jun 9; 119(22): 2894–903
Kloner RA, Watkins VS, Costigan TM, et al. Cardiovascular profile of tadalafil, a new PDE5 inhibitor [abstract no. 707]. J Urol 2002; 167 (4 Suppl.): 176
Hutter Jr AM, Kloner RA, Watkins VS, et al. Blood pressure and cardiovascular effects of tadalafil, a new PDE5 inhibitor [abstract no. P-302]. Am J Hypertens 2002; 15 (4 Pt 2): 140A
Angulo J, Gadau M, Fernandez A, et al. IC351 enhances nitric oxide-mediated relaxation of human arterial and trabecular penile smooth muscle [abstract no. 1133]. Diabetologia 2001; 44 Suppl. 1: A295
Gbekor E, Bethell S, Fawcett L, et al. Phosphodiesterase 5 inhibitor profiles against all human phosphodiesterase families: implications for use as pharmacological tools [abstract no. 967]. J Urol 2002; 167 (4 Suppl.): 246
Kloner RA, Mitchell MI, Bedding A, et al. Pharmacodynamic interactions between tadalafil and nitrates compared with sildenafil [abstract no. 708]. J Urol 2002; 167 (4 Suppl.): 176
Corbin JD, Beasley A, Blount MA, et al. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 2005 Sep 2; 334(3): 930–8
Francis SH. Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res 2005 Sep 31; 17(5): 467–8
Patterson B, Bedding A, Jewell H, et al. Dose-normalised pharmacokinetics of tadalafil administered as a single dose to healthy volunteers [abstract no. 600]. Eur Urol Suppl 2002; 41(1): 152
Wrishko RE, Dingemanse J, Yu A, et al. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol 2008 May; 48(5): 610–8
Spence R, Mandagere A, Harrison B, et al. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci 2009 May 19; 98(12): 4962–74
Patterson B, Bedding A, Jewel H, et al. The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351) [abstract no. 120]. Int J Impot Res 2001; 13 Suppl. 4: S43
Pepke-Zaba J, Beardsworth A, Chan M, et al. Tadalafil therapy and health-related quality of life in pulmonary arterial hypertension. Curr Med Res Opin 2009 Oct; 25(10): 2479–85
European Medicines Agency. Committee for medicinal products for human use post-authorisation summary of positive opinion for adcirca [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/opinion/Adcirca_66932509en.pdf [Accessed 2009 Jan 6]
Acknowledgements and Disclosures
This manuscript was reviewed by: M.M. Hoeper, Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; U. Thadani, Department of Medicine, University of Oklahoma Health Services Center, Oklahoma City, Oklahoma, USA.
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
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Croxtall, J.D., Lyseng-Williamson, K.A. Tadalafil. Drugs 70, 479–488 (2010). https://doi.org/10.2165/11204580-000000000-00000
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DOI: https://doi.org/10.2165/11204580-000000000-00000