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Evaluating the PDE5 inhibitors: what are the differences?

Currently, 3 oral phosphodiesterase type 5 (PDE5) inhibitors are available for treatment of men with erectile dysfunction (ED)--sildenafil, vardenafil, and tadalafil. Each has favorable pharmacokinetic and pharmacodynamic profiles and each is effective in a wide range of patients. Although differentiating the 3 drugs may be useful, so far there are limited data on which to base any firm conclusions regarding potential differences. To date, no controlled, head-to-head clinical trials compare the drugs to one another. So how does a clinician choose which PDE to give a specific patient? Does it, in fact, make a difference which medication is prescribed? This article summarizes the most pertinent findings to date about the drugs' general safety and efficacy in men with mild-to-severe ED.

Similar track records, albeit of unequal length

Sildenafil was approved by the US Food and Drug Administration in March, 1998, followed by vardenafil in August 2003, and tadalafil in November 2003. Sildenafit has a 7-year track record of safety and efficacy. Because sildenafil has been available so much longer than vardenafil and tadalafil, there are far more studies about its safety and efficacy. Nonetheless, several reviews of existing data have found that vardenafil and tadalafil appear to have the same efficacy as sildenafil. (1-3) The drugs' side-effect profiles also appear similar. As mentioned in earlier articles in this issue, none of the 3 agents should be used with nitrates.

A 12-week, randomized, placebo-controlled study of sildenafil, 50 mg, found that 65% of intercourse attempts by those in the treated group were successful as opposed to 20% of attempts by those in the placebo group. (4) A 12-week clinical study of vardenafil showed 65% of intercourse attempts successful at doses of both 10 and 20 mg, compared with 32% of attempts by those receiving placebo. (5) A 12-week efficacy study of tadalafil found successful intercourse rates of 61% with a 10-mg dose, and 68% to 75% with 20 mg. Thirty-two percent of intercourse attempts were successful in this trial's placebo group. (6)

In his review, Sussman concludes that sildenafil, vardenafil, and tadalafil all confer benefits over placebo in healthy men, and are "generally safe and well tolerated." (3) Gresser and Gleiter note, however, that there are not sufficient data to evaluate adverse effects of the 2 newcomers, particularly on their use in high-risk groups and over the long term. (1)

Differences in pharmacokinetics

Selectivity

One area of marked differences in the PDE inhibitors is their selectivity. The selective inhibition of PDE5 prevents the breakdown of cyclic guanosine monophosphate , allowing the relaxation of the smooth muscle cells in the corpus cavernosum. There are 11 families of PDEs. Sildenafil and vardenafil have excellent selectivity for PDE5 versus all PDEs, except PDE6 (TABLE 1), which is an enzyme involved in phototransduction in the retina. Both sildenafil and vardenafil have been found to have dose-related impairment of color discrimination (blue/green)--a finding consistent with the lower selectivity for, and therefore inhibition of, PDE6. (7,8)

Tadalafil is a weak inhibitor of PDE6 and is associated with less than 0.1% occurrence of color vision abnormalities. (2) It is selective for PDE5 but also for PDE11, which is found in the cardiac myocytes, pituitary gland, and testes. (7) It is unclear whether the inhibition of PDE11 has any significant clinical consequences, and further long-term studies are needed.

Absorption

One notable difference among the drugs is their rate of absorption after a high-fat meal. Peak plasma concentrations, or Cmax, of drugs may be affected by comorbid conditions, concomitant medications, or ingestion of food. (12) If sildenafil is taken with a high-fat meal, the Cmax is reduced by about 29% and delays the time to achieve peak plasma concentration, or Tmax, by about 1 hour. (13) This may result in delayed onset of action or reduced efficacy. In fact, in his review of pharmacokinetics, pharmacodynamics, and efficacy of PDE5 inhibitors, Sussman suggests that this drug/food interaction may be a cause for treatment failure in men who do not realize they should take sildenafil on an empty stomach for best results. (3)

In one study of vardenafil taken with a high-fat meal, Cmax was reduced by between 18% and 50% and Tmax was delayed by about 1 hour. (14) However, in the same study, when vardenafil was taken with a moderate-fat meal, there were no clinically significant effects on absorption. The authors conclude that dosage changes were not warranted based on the wide therapeutic index and the efficacy observed with vardenafil in phase III studies that were not restricted with respect to food.

Tadalafil's absorption is unaffected by high-fat food and can be ingested without regard to food intake. (3)

Half-lives

Another interesting difference among the 3 available PDE5 inhibitors is their half-lives. Tadalafil has a half-life that is 4 to 5 times that of the other 2 PDE5 inhibitors. (7) This causes tadalafil to have a longer duration of action, allowing couples to achieve intercourse up to 36 hours postdose as opposed to 4 hours or so after taking sildenafil or vardenafil. (2) However, it is unknown whether the longer half-life also bears additional risk; for example, risks from longer exposure to the drug or for drug interactions.

Onset of action

There do not appear to be significant differences in the onset of action among the 3 PDE5 inhibitors. Sildenafil's onset of action may be as fast as 11 minutes. (15) In one study, 35% and 51% of patients taking sildenafil had 1 or more erections sufficient for intercourse within 14 and 20 minutes of dosing, respectively. (3) Vardenafil has a rapid onset of action, in which erections sufficiently rigid for eventual intercourse completion can be achieved as early as 16 minutes after ingestion. In studies of tadalafil, the onset of action has been found to be from 16 to 30 minutes after ingestion. (6,16.17)

Changes in erectile function

In their quest for a "sensible comparison criterion," Gresser and Gleiter used changes in erectile function from baseline in comparison with placebo, which were recorded uniformly in the studies they examined, using the International Index of Erectile Function (IIEF) questionnaire. (1) They noted that, in a study by Porst et al, 80% of ED patients who received a 20-mg dose of vardenafil had an improved ability to achieve an erection, as did 84% of ED patients in Goldstein et al's 1998 study of sildenafil (100 mg). (18,19) This is consistent with results from 81% of patients receiving 25 mg tadalafil in a 2001 study by Padma-Nathan et al. (16)

Adverse effects

The adverse-event profiles of all 3 PDE5 inhibitors are similar, with headache, flushing, and dyspepsia being the most commonly reported (TABLE 2). As mentioned, all of these drugs are contraindicated with the administration of nitrates. According to Gresser and Gleiter, the events are "similarly frequent, similarly severe, and similarly dose-dependent" among the 3 drugs. (1)

McCullough reported that tadalafil was associated with up to a 12% occurrence of myalgia/back pain compared with placebo, whereas sildenafil's rate is 0.9%. (7) Vardenafil has not been associated with back or muscle pain in any studies to date. (7) Gresser and Gleiter hypothesize that the back and muscle pain are associated with tadalafil's inhibition of PDE11. (1)

As McCullough points out, it is "unwise to make far-reaching conclusions" about safety until there is more experience with the newer agents. (7) However, sildenafil is known to have a proven safety track record after 7 years of experience in more than 20 million patients.

Sustained efficacy

Hellstrom et al evaluated the effectiveness of vardenafil in a 6-month, randomized, fixed-dose (5, 10, or 20 mg) parallel-group trial that included 1311 men with ED of more than 6 months' duration. (20) The primary efficacy variables were the IIEF erectile function domain, the Sexual Encounter Profile (SEP) mean per patient success rates for penetration (Question 2), and maintenance of erections (Question 3). All vardenafil doses were significantly superior to placebo for all efficacy measures. Improvements versus placebo were noted early and were sustained or increased through the end of the study. The 10- and 20-mg vardenafil doses were significantly superior to placebo at all time points for all efficacy variables (P<.01), and all doses were superior to placebo at endpoint (P<.001).

The IIEF includes a specific erectile function (EF) domain. Scores on this domain can be divided into 4 categories of severity; none, mild, moderate and severe. In the above study, mean EF domain scores changed by at least one category in 2102 men with mild-to-severe ED who took tadalafil, 10 mg or 20 mg, in 11 randomized, double-blind, placebo-controlled trials lasting 12 weeks. (21) The higher dose allowed more than 70% of participants with mild dysfunction and 40% with severe dysfunction to return to normal EF domain scores by the study endpoint.

Patients receiving either dose of tadalafil had a significant mean improvement of 6.5 and 8.6, respectively, in the IIEF EF domain from baseline (P<.001 versus placebo). At both doses, the mean success rate for intercourse attempts (SEP Question 3) was 58% and 68%, respectively, compared with 31% in the placebo group (P<.001), and 71% and 84% reported improved erections at the endpoint versus 33% on placebo (P<.001). Tadalafil was effective up to 36 hours after dosing and was effective regardless of disease severity and causes in patients of all ages.

Men with comorbid disease

The efficacy of PDE5-inhibitor therapy in men with comorbidities is discussed by other authors in this supplement. For example, Sadovsky reviews their role in men with cardiovascular disease, diabetes, and depression, and in those who have undergone prostatectomy. DeBusk and Kloner advocate their prohibition in men with ischemic heart disease taking nitrates, while White places them within the context of men being treated for hypertension.

As reported by the Second Princeton Consensus Conference, studies of PDE5-inhibitor therapy in men with ED demonstrated no increase in myocardial infarction or death compared with expected rates. Studies of patients with coronary artery disease or heart failure were also on PDE5-inhibitor therapy did not exhibit worsening ischemic coronary vasoconstriction or diminished results on exercise testing or cardiac catheterization.

When sildenafil fails

Recently reported results from the Men's Attitudes Toward Life Events and Sexuality (MALES) study indicate that approximately 50% of patients who start sildenafil continue therapy, whereas 23% express dissatisfaction with it due to suboptimal hardness of erections (34%), complete failure of therapy (34%), and poor treatment reliability (22%). (22) These results are consistent with previous studies, which also demonstrated relatively high discontinuation rates with sildenafil over the long term. (23-25)

On the other hand, more than half of 137 men who had not had success with sildenafil experienced improved results after reeducation and counseling, which included information on how to take the drug correctly and on titration to the maximum dose. (26)

The PROVEN (Patient Response with VardENafil) trial was a multicenter, double-blind study in which more than 450 men with moderate-to-severe ED who did not respond to sildenafil were randomized to receive either placebo or vardenafil (10 mg as needed for 4 weeks, with an option to continue on this dose or titrate to 5 mg or 20 mg). (25) All patients met rigorous inclusion criteria, including nonresponse to sildenafil, 100 mg. At baseline, 90% of patients in the vardenafil treatment arm were diagnosed with moderate or severe ED. Primary endpoints included the IIEF erectile function domain score, SEP questions 2 and 3, and a global assessment question about improvement of erectile function.

After 12 weeks, vardenafil produced statistically and clinically significant improvements in all of these measures (TABLE 3). Patients treated with vardenafil experienced an 8-point increase in EF domain score from 9.3 at baseline to 17.6 at endpoint (approximately 2 severity categories of change). Diary results in response to SEP question 2 indicated a statistically significant improvement in penetration rate with vardenafil from 28.5% at baseline to 62.3% after 12 weeks (P<.001). The improvement in the rate of successful intercourse was 46.1% for vardenafil at 12 weeks versus 10.1% at baseline (P<.001). Vardenafil also significantly improved EF in 61.8% of patients who were nonresponders to sildenafil.

These results provide a clear and controlled demonstration of the common clinical observation that a patient who fails on one PDE5 inhibitor may respond to another. The potential utility of switching patients from one oral PDE5 inhibitor to another is also supported by the fact that the safety profiles for all of these drugs are similar.

It is also possible that vardenafil's higher selectivity than either sildenafil or tadalafil for PDE5 versus other PDEs may offer tolerability advantages not yet reflected in safety data for these drugs. (23)

Conclusion

As more experience is gained with the 2 newer oral PDE5 inhibitors, it may become possible to select an agent that is most suitable for a given patient based on pharmacokinetics, pharmacodynamics, efficacy, and safety. Until then, we can say in general that

* For patients who are concerned about the timing of sexual activity, determine whether rapid onset of action or extended duration of action is of greater importance. Tadalafil has the longest duration of action, with a mean half life of 17.5 hours.

* For patients who routinely enjoy a hearty meal before sex, choose a PDE5 inhibitor that will not be affected by the ingestion of high-fat food which may delay the Tmax.

* For patients who are advised against sexual intercourse due to severe underlying cardiac disease, PDE5 inhibitors are not recommended.

* For patients who are receiving any form of nitrate therapy, the use of PDE5 inhibitors is contraindicated.

KEY POINTS

* The 3 available oral PDE5 inhibitors are similar in terms of onset of action, efficacy (eg, change in erectile function), and side effects, although tadalafil is more likely to be associated with backache or muscle pain.

* Sildenafil is the strongest inhibitor of PDE6, which may lead to impaired color discrimination. Tadalafil also inhibits PDE11, but associated clinical consequences are unknown.

* Consumption of high-fat foods impairs the absorption of sildenafil and to a lesser degree vardenafil.

* Tadalafil has a longer half-life and duration of action than sildenafil and vardenafil.

* Sildenafil, which has accrued the most clinical experience (both in numbers of patients and time) has a failure rate that can be improved by educating or counceling the patient or switching to another agent.

References

(1.) Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil-review of the literature. Eur J Med Res. 2002;29:435-446.

(2.) Seftel AD. Phosphodiesterase type 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. Clin Cardiol. 2004;27 (suppl 1):114-119.

(3.) Sussman DO. Pharmacokinetics, pharmacodynamics, and efficacy of phosphodiesterase type 5 inhibitors. J Am Osteopath Assoc. 2004;104(suppl 4):$11-$15.

(4.) Padma-Nathan H, Steers WD, Wicker PA. Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: A double-blind, placebo-controlled study of 329 patients. Sildenafil Study Group. Int J Clin Pract. 1998;52:375-379.

(5.) Hellstrom WJ, Gittelman M, Karlin G, et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl. 2002;23:763-771.

(6.) Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol. 2002;168:1332-1336.

(7.) McCullough A. An update on the PDE-5 inhibitors (PDE-5i). J Androl. 2003;24(suppl):S52-S58.

(8.) Impotence agents. In: Drug Facts and Comparisons. St. Louis, Mo: Wolters Kluwer Health, Inc; 2004:579-584a.

(9.) Sildenafil. [US prescribing information]. New York, NY: Pfizer Inc.; 2002.

(10.) Tadalafil. [US prescribing information]. Indianapolis, Ind: Lilly ICOS LLC; 2003.

(11.) Vardenafil. [US prescribing information]. West Haven, Conn: Bayer HealthCare. Research Triangle Park, NC: GlaxoSmithKline; 2003.

(12.) Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract. 2002;56:453-459.

(13.) Padma-Nathan H, Guillain F. Oral drug therapy for erectile dysfunction. Urol Clin North Am. 2001;28:321-334.

(14.) 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.

(15.) Kendirci M, Bivalacqua TJ, Hellstrom WJ. Vardenafil: a novel type 5 phosphodiesterase inhibitor for the treatment of erectile dysfunction. Expert Opin Pharmacother. 2004;5:923-932.

(16.) Padma-Nathan H, Rosen RC, Shabsigh R, Saikali K, Watkins V, Pullman B. Cialis (IC351) provides prompt response for the treatment of men with erectile dysfunction (ED). J Urol. 2001;165(suppl):224.

(17.) 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.

(18.) Porst H, Rosen R, Padma-Nathan H, et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res. 2001;13:192-199.

(19.) Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404.

(20.) Hellstrom WJ, Gittelman M, Karlin G, et al. Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. Urology. 2003;61(suppl 1):8-14.

(21.) Carson CC, Rajfer J, Eardley I, et al. The efficacy and safety of tadalafil: an update. BJU Int. 2004;93:1276-1281.

(22.) Eardley I, Rosen R, Fisher WA, et al. Attitudes toward treatment of erectile dysfunction: results from the MALES study. Eur Urol. 2003;44(suppl 2):97.

(23.) Sheu JY, Chen KK, Lin AT, et al. Long-term efficacy and safety of sildenafil for patients with erectile dysfunction. J Chin Med Assoc. 2003;66:480-486.

(24.) Souverein PC, Egberts AC, Meuleman EJ, et al. Incidence and determinants of sildenafil discontinuation: the Dutch cohort of sildenafil users. Int J Impot Res. 2002;14:259-265.

(25.) Carson CC, Hatzichristou D, Carrier S, Lording D, Young J, Murdoch M for the Vardenafil Study Group. Vardenafil exhibits efficacy in men with erectile dysfunction unresponsive to prior sildenafil therapy: results of a phase III clinical trial-Patient RespOnse with VardENafil in sildenafil non-responders (PROVEN). Int J Impot Res. 2003;15(suppl 5):$175.

(26.) Broderick GA. Oral pharmacotherapy and the contemporary evaluation and management of erectile dysfunction. Rev Urol. 2003;5(suppl 7):$9-$20.

Culley C. Carson, MD

University of North Carolina School of Medicine

Chapel Hill, NC

Raymond C. Rosen, PhD

Robert Wood Johnson Medical School

New Brunswick, NJ
TABLE 1
Selectivity ratios of PDE inhibitors

        Sildenafil   Vardenafil   Tadalafil

PDE1        80          257        >10,000
PDE2      >7500       >10,000      >10,000
PDE3       4400         3600       >10,000
PDE4       1800         5700       >10,000
PDE5        1            1            1
PDE6        10          224          780
PDE7       5160       No data      >10,000
PDE8     >10,000      No data      >10,000
PDE9       2796       No data      >10,000
PDE10      1123         447        >10,000
PDE11      346          203          5.5

Adapted from Broderick GA. Rev Urol. 2003;5(suppl 7):S9-S20. (26)

TABLE 2
Adverse events reported most often in controlled
clinical trials of PDE5 inhibitors

Adverse event     Sildenafil      Placebo      Tadalafil
                  (25-100 mg)    (5-20 mg)
                   (N = 734)     (N = 725)    (N = 1180)

Headache              16%           4%          11-15%
Flushing              10%           1%           2-3%
Nasal                 4%            2%           2-3%
congestion/
rhinitis
Dizziness             2%            1%            <2%
Dyspepsia             7%            2%           4-10%
Back pain             >2%           >2%          3-6%

Adverse event       Placebo     Vardenafil      Placebo
                   (5-20 mg)
                   (N = 476)    (N = 2203)    (N = 1199)

Headache              5%            15%           4%
Flushing              1%            11%           1%
Nasal                 1%            9%            3%
congestion/
rhinitis
Dizziness             <2%           2%            1%
Dyspepsia             1%            4%            1%
Back pain             3%            2%           1.7%

Adapted from PDE5-inhibitor US prescribing information. (9-11)

TABLE 3
Efficacy of vardenafil in 463 men who failed treatment with sildenafil

Efficacy measure                   Placebo              Vardenafil
 (least-squares mean)   Baseline    12 wk    Baseline     12 wk

EF domain (last
  observation carried
  forward                 9.6       10.5       9.3        17.6
SEP2 (% yes)             31.8       29.9      28.5        62.3
SEP3 (% yes)             11.7       16.1      10.1        46.1
GAQ                       NA        14.7       NA         61.8

Efficacy measure
 (least-squares mean)    P value

EF domain (last
  observation carried
  forward                <0.001
SEP2 (% yes)             <0.001
SEP3 (% yes)             <0.001
GAQ                      <0.001

EF = erectile function; SEP = Sexual Encounter Profile Question 2:
Success rate for penetration, Question 3: Maintenance of erections);
GAQ = general assessment question (Has treatment improved erections?);
NA = not applicable.

Adapted from Carson CC, et al. Int J Impot Res. 2003; 15(suppl 5);
S175. (25)
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Title Annotation:oral phosphodiesterase type 5 inhibitors
Author:Carson, Culley C.; Rosen, Raymond C.
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Dec 1, 2005
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