| European Urology - Treatment of Erectile Dysfunction with Chronic Dosing of Tadalafil |
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| Tuesday, 01 August 2006 | ||
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Volume 50, Issue 2, Pages 215-217 (August 2006) The medical management of erectile dysfunction (ED) was re-defined following the recognition that the signalling system of nitric oxide–cyclic guanosine-3′5′-monophosphate (NO-cGMP) was pivotal in the production of the arterial dilation and venous occlusion necessary to attain and sustain an erection. In parallel with this new understanding of the mechanism of penile erection, several phosphodiesterase type 5 inhibitor drugs (PDE-5s), which inhibit the breakdown of cGMP producing vasodilatation and improve endothelial cell function, have been developed and demonstrated to be effective in treating erectile dysfunction. However, the paradigm for the medical treatment of erectile dysfunction remains unchanged in that it includes on-demand dosing of medication. Whilst on-demand dosing reflects the intermittent nature of sexual intercourse, currently is more cost-effective than chronic dosing and may be reasonable for many men with erectile dysfunction, it ignores the potential corporal, cardiovascular and relationship benefits of chronic PDE-5 inhibitor dosing. Penile vascular disease is the most common cause of erectile dysfunction, accounting for up to 80% of cases. Abnormalities of the NO-cGMP–signalling system attributable to endothelial dysfunction are present in atherosclerosis and play an important role in the pathophysiology of erectile dysfunction [1], [2]. Endothelial dysfunction may be present in patients with ED even in the absence of significant cardiac risk factors, suggesting that ED may be the first clinical manifestation of cardiovascular disease [3]. It is speculative—but likely—that chronic PDE-5 inhibitor treatment will improve endothelial function and cardiovascular health in general. Sildenafil has been reported to improve endothelium-dependent, flow-mediated vasodilatation in smokers and in patients with diabetes mellitus or chronic heart failure [4], [5], [6]. Chronic therapy with tadalafil has been reported to improve endothelial function and erectile function in patients with and without cardiovascular risk factors [7], [8]. Chronic treatment with a PDE-5 inhibitor may produce functional tissue modifications involving upregulation of either muscarinic receptors or the transduction mechanisms leading to the activation of endothelial nitric oxide synthase [9]. In addition to their role in the treatment of erectile dysfunction and pulmonary hypertension, recent reports suggest a potential role exists for the use of daily PDE-5 inhibitors in the treatment of other forms of cardiovascular disease such as hypertension. Although administration of PDE-5 inhibitors to healthy normotensive subjects results in only modest lowering of systolic and diastolic arterial pressures, a greater decrease may occur in subjects with hypertension and increased systemic vasoconstriction related to raised levels of angiotensin II, especially if angiotensin II antagonists are co-prescribed [10]. The prolonged half-life of tadalafil (17.5hours) and the resultant prolonged 36-hour period of responsiveness constitute an ideal pharmacokinetic profile for chronic dosing, compared with short half-life PDE-5 inhibitor drugs. Over a dose range of 2.5 to 20mg, tadalafil systemic exposure increases proportionally with the dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose. In the first randomised placebo controlled trial of daily dosing of tadalafil, Porst et al. [11] report that once-daily dosing of tadalafil 5 and 10mg significantly improved all erectile function primary and secondary outcome measures, compared with placebo (p<0.001), and was well tolerated. Successful completion of intercourse was reported in 72.8% of attempts with tadalafil 10mg, compared with 36.7% with placebo. Furthermore, the EF domain score was increased into the normal range (≥26) in 50.5% of subjects treated with tadalafil 10mg. Of particular interest is the report that changes from baseline to end point were similar for both doses of tadalafil, suggesting 5mg as the optimal starting dose. The frequency of treatment emergent adverse events was similar to that reported in an earlier integrated analysis of 11 on-demand tadalafil trials and included dyspepsia, headache, dyspepsia, back pain and myalgia. These adverse effects were mild to moderate in severity in 86.6% of subjects, prompted discontinuation of the study in 3.4% of subjects and reflect the pharmacologic action of tadalafil as a PDE-5 inhibitor. Efficacy, tolerability and preference for chronic dosing of tadalafil have been reported previously by other authors [12], [13], [14] using once-daily or alternate day dosing regimens in uncontrolled, open-label design studies. Daily dosing of tadalafil (10–20mg) was reported as an effective salvage therapy for patients unresponsive to on-demand tadalafil [12]. In a study population of men with severe, predominantly organic ED and a high incidence of vascular risk factors who satisfied rigorous criteria for on-demand tadalafil treatment failure, daily dosing of tadalafil significantly enhanced all efficacy outcome variables, compared with baseline and on-demand tadalafil. In a second study, the efficacy and safety of on-demand tadalafil 20mg and daily tadalafil 10mg were compared by using a 26-week, open-label, parallel arm, crossover study design [13]. The mean change from baseline for all erectile function primary and secondary outcome measures was significantly higher for daily-dosed tadalafil, compared with on-demand tadalafil (p<0.05). At the completion of the study, 72% preferred daily tadalafil. The 14 European country, multicenter, crossover, open-label SURE study examined subject preference for tadalafil taken on-demand or 3 times/week [14]. The authors reported that both regimens were efficacious and well tolerated, and that 42.2% of subjects preferred the 3 times/week treatment. However, differences in study design, duration of treatment, dosing regimens, study population demography, eligibility criteria, study outcome measures and methods of data analysis make comparison between studies difficult. Furthermore, preference studies have inherent methodologic flaws, resulting in poor internal validity attributable to study design biases and confounding errors, thus making generalization of their results to men seeking treatment for ED difficult or impossible. Whilst chronic dosing of tadalafil may have a potential role as a treatment for ED, its utility is limited by current high cost and the reality that the average 5–6 times per month intercourse requirements of the typical ED patient are met adequately by on-demand tadalafil. Tablet splitting, although not recommended by the manufacturer, is common in daily office practice and may reduce the cost of chronic dosing to a level acceptable to many patients. A potential role exists for chronic dosing of tadalafil, alone or in combination with on-demand tadalafil or intracavernous injection therapy, in the salvage of on-demand PDE-5 failure in patients with severe and challenging ED such as diabetic ED, severe vasculogenic ED, post-radical prostatectomy ED or comorbid hypertension. Of particular interest is the putative place of chronic dosing of tadalafil for ED prophylaxis in men following a nerve-sparing radical retropubic prostatectomy (NSRRP) in which intraoperative neurapraxia may delay recovery of cavernous nerve function and return of potency for up to 2 years. It is widely accepted that early ED prophylaxis/treatment may interrupt the progressive apoptotic loss of corporal smooth muscle and the increased deposition of extracellular matrix attributable to chronic, corporal, hypoxia-induced, increased production of transforming growth factor-β1, which results in the eventual development of structurally based corporeal veno-occlusive dysfunction. Levine et al. [15] reported that nightly administration of sildenafil post-NSRRP increased the return of spontaneous erections 6-fold, compared with placebo. Randomised, open-label, comparator and patient PDE-5 preference studies have highlighted the importance that patients place on the ability to achieve an erection several hours after dosing, as seen with long half-life PDE-5 inhibitors such as tadalafil, and report higher levels of overall patient satisfaction, compared with sildenafil [16]. With regards to the reestablishment of sexual spontaneity as an important treatment attribute, some patients may chose chronic dosing regimens to almost completely remove the need for planning a sexual encounter. Furthermore, younger men with psychogenic ED often report on-demand PDE-5 inhibitor failure on those occasions when they needed to plan sexual activity; their concern that on-demand PDE-5 inhibitors may not be effective exacerbate already present high levels of performance anxiety. Interim tadalafil chronic-dosing regimens alone or in combination with cognitive behavioural therapy potentially may offer these patients a higher level of efficacy assurance and improved treatment outcomes, and may improve the potential for restoration of potency. In conclusion, treatment of ED with daily tadalafil appears effective, safe and well tolerated. Chronic dosing regimens of tadalafil may have a role in the routine management of selected patients with ED, in the management of treatment refractory ED or as post-NSRRP ED prophylaxis. It may be associated with higher levels of patient and partner sexual, and overall satisfaction and consequential improvements in the quality of relationships. Further controlled efficacy, tolerability and patient preference studies are required to determine the optimal dose, the frequency of chronic dosing, the time course for improvement in erectile function, the potential for the development of drug tolerance and the full spectrum of patient and partner psychological and relationship benefits.Conflicts of interestDr McMahon is an investigator, member of an advisory board and/or speaker's panel for Johnson & Johnson, Janssen-Cilag, Ortho McNeil, Pfizer, Icos-Lilly and Bayer. References 1. Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol. 1991;146:238–240. 2. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989;320:1025–1030. Chris G. McMahon Sydney, NSW, Australia published online 30 March 2006.
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