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Dr Nusbaum is a consultant for Bayer Corporation and receives research support from Pfizer Inc. She is also on the speakers bureau of Bayer Corporation and Pfizer Inc.
Correspondence to Margaret R. H. Nusbaum, DO, MPH, Department of Family Medicine, University of North Carolina at Chapel Hill, Manning Dr, Chapel Hill, NC 27599-7595. E-mail: margaret_nusbaum{at}med.unc.edu
No head-to-head studies have been conducted with the phosphodiesterase type 5 (PDE5) inhibitors to date. Results of noncomparative studies, however, suggest that tadalafil and vardenafil hydrochloride are at least as effective as sildenafil citrate in improving erections and increasing the number of successful intercourse attempts in men with erectile dysfunction (ED) at all levels of severity. By facilitating a sexual response, PDE5 inhibitors lend naturalness to sexual activity and may permit couples to return to their previous sexual lifestyle. By providing a broader window of opportunity, a longer-acting PDE5 inhibitor such as tadalafil adds to the variety of options currently available in managing ED with PDE5 inhibitors. This option offers increased flexibility by minimizing the need to plan sexual activity; allowing more time for intimacy or romance before sexual intercourse; and reducing the pressure on the patient to perform.
Recently, the Food and Drug Administration (FDA) approved two new PDE5 inhibitors, tadalafil and vardenafil hydrochloride. These new additions to this class of medications offer increased opportunities for patients who are seeking treatment for ED. The PDE5 inhibitors enable men to regain sexual function and self-esteem, rebuild relationships, and enjoy a greater overall sense of emotional health and well-being.
Most patients with ED select an oral agent as treatment rather than more invasive options (Table 1).2 Even before the advent of sildenafil, about 70% to 80% of patients chose to initiate oral regimens.3,4 The PDE5 inhibitors offered a welcomed breakthrough for men who previously could not effectively achieve or maintain an erection with other first-line medications (eg, androgen therapy, yohimbine), or second-line interventions (eg, vacuum constriction device).
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Overview of Phosphodiesterase Type 5 Inhibitors |
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 Top Overview of Phosphodiesterase... Patient Decisions When Selecting...Clinical trialsCommentReferences |
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Although the PDE5 inhibitors have a similar mechanism of action, significant differences exist between these agents, especially in the areas of selectivity and pharmacokinetics. The most notable differences between these agents—and the ones that most directly address patient preferences—are onset and duration of action (Table 2).
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Sildenafil and Vardenafil—Sildenafil and vardenafil
possess many similarities, though distinctions exist between the two in regard
to selectivity and interactions with food.
Vardenafil and sildenafil may be more effective if the drugs are taken on an empty stomach. Eating a high-fat meal before taking vardenafil or sildenafil increases the time to maximum plasma concentration (tmax) by 60 minutes and reduces the peak plasma concentration (Cmax) by 18% to 50% and 29%, respectively. (In general, an adjustment in dose [sildenafil citrate is available in 25-mg, 50-mg, and 100-mg doses] is not required if patients consume a high-fat meal).6,9-11
Both sildenafil and vardenafil demonstrate a similarly rapid onset of action (Table 2). In clinical trials, sildenafil has shown efficacy as early as 14 to 20 minutes after administration1; vardenafil's onset of action leading to the successful completion of intercourse has been seen as early as 16 minutes after ingestion.9,10,12 Both drugs typically remain effective for a short time. If taken in the fasting state, the tmax for sildenafil is 30 to 120 minutes (median, 60 minutes) after dosing and its terminal half-life is 3 to 5 hours. Clinical efficacy has been observed for upwards of 2 to 3 half-lives, but, for maximum benefit, dosing is recommended approximately 1 hour before sexual activity.9 Similarly, a study of men with ED of no known organic cause indicated that the median tmax of vardenafil was achieved at 0.68 hour to 0.92 hour, with a plasma half-life of less than 1 hour.6,7
Tadalafil—The pharmacokinetic studies on tadalafil
demonstrated that neither the consumption of a high-fat meal nor the timing of
the dosing (morning or evening) had an effect on changes in plasma
concentration or time to maximal
response.13 These
findings suggest that tadalafil can be administered at any time, with or
without food, and regardless of the fat content of the meal, resulting in no
effect on
absorption.13
Tadalafil has a longer median half-life of 17.5 hours, which supports results
from clinical trials indicating a period of responsiveness for 24 to 36 hours
(Table
2).14,15
In a study by Brock and colleagues,14 tadalafil, 20 mg, enabled 73% to 80% of sexual intercourse attempts to be completed successfully (with appropriate sexual stimulation) between 30 minutes and 36 hours after dosing. These findings are consistent with separate placebo-controlled trials demonstrating that tadalafil confers significant effect from 16 minutes to 36 hours postdose.
Even in a study in which men and their partners were restricted to a specific timeframe in which to attempt intercourse, at 24 hours after administration, 57.3% of intercourse attempts by men taking tadalafil were successful, compared with 31.3% of intercourse attempts by men taking placebo (P<.001). The effect was maintained at 36 hours: 60.4% of intercourse attempts in the tadalafil-treated group were successful versus 29.9% in the control group (P<.001).15
These studies underscore the pharmacokinetic differences between sildenafil, tadalafil, and vardenafil. A better understanding of these characteristics plays an integral role in the treatment-selection process that is best for the patient's and partner's sexual needs and lifestyle requirements. These differences between the duration of action of tadalafil and that of the other PDE5 inhibitors may offer patients a new opportunity when selecting treatment options: A longer-acting agent may provide a greater degree of flexibility when planning sexual activity.
Results of a survey of men with ED16 indicate that the following factors are important for successful treatment of ED:
The results of other research support and augment these findings. In reporting the factors that would influence their initial choice of therapy, men participating in independent focus groups cited not only the desired naturalness, but also other nonmedical factors such as reversibility of the drug's effect, discreetness, convenience, and acceptability of the therapy by the patient's partner.17
By facilitating a sexual response, PDE5 inhibitors lend increased naturalness to sexual activity and may permit couples to return to their previous sexual lifestyle. By providing a broader window of opportunity, a longer-acting PDE5 inhibitor such as tadalafil may result in successful management of ED by:
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Patient Decisions When Selecting a Phosphodiesterase Type 5 Inhibitor |
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TopOverview of Phosphodiesterase...Patient Decisions When Selecting...Clinical trialsCommentReferences |
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Using a 5-point Likert scale, 88% of respondents ranked the feature, "Duration of time in which to have sex (length of medication's effectiveness)" as "very important" or "extremely important." This response rate correlated highly with several other attributes, which, when taken together, reflect overall improvements in relationship quality and suggest that the length of a medication's effectiveness may be a predictor of improved, satisfying sexual relations.16
The Harris Poll also showed that more than a third of survey respondents stated that what they most want from a medication for ED is that it provide them with the ability to have quality erections, an important contributor to increased confidence and self-esteem. Ninety-three percent of respondents ranked "The length of time I am able to maintain an erection" as "Very Important" or "Extremely Important."16
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Clinical trials |
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TopOverview of Phosphodiesterase...Patient Decisions When Selecting...Clinical trialsCommentReferences |
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After a treatment-free screening period of approximately 1 week, patients were instructed to take their assigned medication up to once a day, with water, on an as-needed basis, according to instructions specific to each respective treatment (those in the tadalafil group were told that they could take the drug up to 24 hours before planned sexual activity).
Preference was not affected by patients' age or duration of ED, nor did it differ according to the order in which treatments were received or previous exposure to sildenafil (Table 3).18 Preference was similarly unaffected by the presence of cardiovascular disease or diabetes: 35 (64.8%) of 54 men with these comorbidities preferred tadalafil, as did 91 (66.9%) of 136 men without these conditions.18
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Govier and colleagues18 noted that the 24-hour window of clinical responsiveness observed among patients taking tadalafil might suit a range of couples for whom a more natural, less-planned encounter is preferable. They observed that the ability to initiate sexual activity at almost any time of day after tadalafil dosing, without considering the timing of one's last meal, may meet the needs of patients who value simplicity and convenience in a drug regimen.18
Preliminary results of a 4-week randomized multicenter trial of sildenafil citrate, 100 mg; tadalafil, 20 mg, and vardenafil hydrochloride, 20 mg,19 also suggest that most patients with ED would select one of the newer PDE5 inhibitors. Based on an evaluation of International Index of Erectile Function (IIEF) scores, the study found that 83% of men taking the maximum dose of vardenafil had improved erections, compared with 72% and 70%, respectively, for sildenafil and tadalafil.19
By contrast, a recent study by Claes20 showed that only 26% of regular users of sildenafil would choose to switch to one of the newer PDE5 inhibitors. Employing total IIEF scores and Q3 and Q4 categories of the ability to achieve and maintain an erection, sildenafil-treated patients with ED who switched their prescriptions to either tadalafil or vardenafil said that their erections did not improve significantly using the new medications. Only 19 of the 91 men in the study said they would make the switch from sildenafil, mainly because of its fewer side effects.20
Ströberg and colleagues21 also sought to determine the proportion of patients currently taking sildenafil who, after having been switched to tadalafil for a 6-week initiation phase followed by a 3-week assessment phase, would elect to either return to sildenafil citrate at their customary dose (25 mg, 50 mg, or 100 mg) or continue taking tadalafil for an additional 6 months.
Patients reported, by a ratio of approximately 9:1, a preference to continue therapy with tadalafil. Of 147 men completing a 3-week sildenafil assessment phase and a 3-week tadalafil assessment phase, 133 (90.5%) elected to receive tadalafil in the subsequent 6-month extension phase, compared with 14 men (9.5%) who elected to return to treatment with sildenafil (P<.001). This preference for tadalafil emerged irrespective of age, severity of ED, etiology of ED, and use of sildenafil at entry into the study (50 mg, 90%; 100 mg, 89%).21
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Comment |
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TopOverview of Phosphodiesterase...Patient Decisions When Selecting...Clinical trialsCommentReferences |
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When selecting therapy for ED, it is also important to consider the varied needs and expectations of individual patients and their partners. With the availability of several PDE5 inhibitors for management of ED, patients and their partners will play a pivotal role in selecting treatment options. The eventual selection of a specific agent is predicated on several properties of the drug (eg, onset and duration of activity, tolerability, and convenience in dosing) that offer the most satisfaction to a man and his partner, and leads to long-term improvement in the quality of their lives after restoration of sexual activity. It also is important to recognize that treatment outcomes may vary among different patient populations.
With the addition of newer PDE5 inhibitors into the therapeutic armamentarium for ED, the differentiating properties of these agents—with respect to safety, efficacy, and pharmacokinetic profiles—may help physicians identify the most appropriate therapy to optimize patient care and outcomes.
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References |
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TopOverview of Phosphodiesterase...Patient Decisions When Selecting...Clinical trialsCommentReferences |
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2. Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: results of the 'Cologne Male Survery.' Int J Impot Res. 2000;12:305 -311.[Medline]
3. Hanash KA. Comparative results of goal oriented therapy for erectile dysfunction. J Urol.1997;157:2135 -2138.[Medline]
4. Jarow JP, Nana-Sinkam P, Sabbagh M, Eskew A. Outcome analysis of goal directed therapy for impotence. J Urol. 1996;155:1609 -1612.[Medline]
5. Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of
sildenafil. J Biol Chem. 1999;274:13729
-13732.
6. Vickers MA, Satyanarayana R. Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus. Int J Impot Res. 2002;14:466 -471.[Medline]
7. Sorbera LA, Martin L, Rabasseda X, Castañer J. Vardenafil. Drugs of the Future.2001;26:141 -144.
8. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802
-1813.
9. Padma-Nathan H, Giuliano F. Oral drug therapy for erectile dysfunction. Urol Clin North Am. 2001;28:321 -334.[Medline]
10. Levitra® (vardenafil HCl) prescribing information. West Haven, Conn: Bayer Pharmaceuticals Corp;2003 .
11. Rajagopalan P, Mazzu A, Xia C, Dawkins R, Sundaresan P. Effect of
high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of
vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of
erectile dysfunction. J Clin Pharmacol. 2003;43:260
-267.
12. Padma-Nathan H, Kaufman J, Taylor T. Earliest time of onset of erections with vardenafil determined in an in-home setting. Abstracts 2003. Prog Urol. 2003;13(3 (suppl 2). Abstract 99.
13. Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351). Poster presented at: 4th Biennial Meeting of the European Society for Sexual and Impotence Research; September 30 to October 3,2001; Rome, Italy.
14. Brock GB, McMahon CG, Chen KK, Costigan T, Shen W, Watkins V, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol. 2002;168:1332 -1336.[Medline]
15. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003;62:121 -126.[Medline]
16. Taylor H, Leitman R, eds. HarrisInteractive. Men with erectile dysfunction (ED) want improved relations with their partners. Health Care News. April 30,2001;1(14).
17. Hanson-Divers C, Jackson SE, Lue TF, Crawford SY, Rosen RC. Health outcomes variables important to patients in the treatment of erectile dysfunction. J Urol. 1998;159:1541 -1547.[Medline]
18. Govier F, Potempa A-J, Kaufman J, Denne J, Kovalenko P, Ahuja S. A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clin Ther. 2003;25:2709 -2723.[Medline]
19. Van Ahlen H, et al. Which PDE5 inhibitor do you prefer? A comparative multicenter study of sildenafil citrate, tadalafil, and vardenafil HCl. Poster presented at: 6th Congress of the European Society of Sexual Medicine; 2003; Istanbul, Turkey. Poster P-079.
20. Claes H. The new PDE5 inhibitors in comparison with sildenafil citrate. Poster presented at: 6th Congress of the European Society of Sexual Medicine; 2003; Istanbul, Turkey.. Poster PS-2-7.
21. Ströberg P, Murphy A, Costigan T. Switching patients with erectile dysfunction from sildenafil citrate to tadalafil; results of a European multicenter, open-label study of patient preference. Clin Ther. 2003;25:2724 -2737.[Medline]
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