About Tadalafil and Vardenafil
Tadalafil is a novel PDE-5 inhibitor developed by the biotechnology company ICOS Corp. in Bothell, USA. Meanwhile, the drug has attained an approval letter from the Food and Drug Administration (FDA), and its marketing is expected in the second half of 2003 in the USA, whereas in Europe the drug was approved just recently. In contrast to sildenafil and vardenafil, the molecular structure of tadalafil is quite different.
This may be the reason that the compound cannot be considered a pure PDE-5 inhibitor but a combined PDE-5/11 inhibitor, because in therapeutic doses as well as PDE-5 also PDE-11 is inhibited. In this connection, it should be mentioned that PDE-11 is found in relevant concentrations in the testicle, the heart, the pituitary and the prostate.
At present it is not clear what the ultimate physiological function of PDE-11 is, and whether inhibition of this enzyme would have any importance in terms of these organs. A further important difference from other PDE-5 inhibitors is the pharmacokinetics of this new drug, which shows a half-life of 17.5 h, more than four times longer than that of the competitors. In very recent studies it has been proven that this drug also has statistically significant efficacy after 36 h, with 60% completed attempts for intercourse as compared with only 30% after placebo.
The integrated data of five placebo controlled, double-blind randomized trials with 1112 patients enrolled, many of them with diabetes and/or hypertension, showed a clear dose-dependent efficacy with 75% success rates (completed coitus) with the 20-mg dose.
In these five trials, the drug-related adverse events were more or less comparable with those related to the other two PDE-5 inhibitors. With the highest dose (20 mg) of tadalafil, the side-effect rate >2% was as follows:
Headache 14% vs. 6% after placebo;
Dyspepsia 10% vs. 2% after placebo;
Back pain 6% vs. 5% after placebo;
Myalgia 5% vs. 2% after placebo;
Nasal congestion 5% vs. 4% after placebo;
Flushing 4% vs. 2% after placebo.
Different from sildenafil, tadalalfil has nearly no impact on retinal PDE-6, which is mirrored by a very low rate of visual disturbances (<1%) in the clinical trials. Considering all the data on tadalafil available to date, there is no doubt that this new PDE-5 inhibitor represents a real alternative to sildenafil, and will challenge this drug.
Vardenafil is also a novel PDE-5 inhibitor developed by Bayer GmbH, Leverkusen, Germany. Meanwhile, this drug has also received an approval letter from the FDA, and its marketing can be expected by 2003 in both the USA and Europe.
Compared with sildenafil, the molecular structure of vardenafil shows at first glance only minor differences. However, these minor differences may be responsible for the fact that, in vitro, the biochemical potency of vardenafil, mirrored by its IC50 (inhibitory concentration giving 50% maximal) for PDE-5, is nine times higher than that of sildenafil.
Therefore, in clinical use, doses of vardenafil yielding comparable efficacy rates to sildenafil are five times lower. In addition, the pharmacokinetics of vardenafil reveals a very short Tmax (time to maximum concentration) allowing the shortest time of onset of erection among all three competing PDE-5 inhibitors. Details of the pharmacokinetics of all three PDE-5 inhibitors are summarized in Table 1.
In a very large placebo-controlled, double-blind randomized phase IIb trial, the efficacy and safety of vardenafil was assessed in a mixed erectile dysfunction population involving 601 patients. About one-third each suffered from psychogenic, mixed or organogenic erectile dysfunction, respectively, and also about onethird each from mild,
moderate or severe erectile dysfunction according to the erectile function domain of the International Index of Erectile Dysfunction (IIEF).
In terms of the most relevant efficacy parameter, question 3 of the sexual encounter profile (SEP), which includes penetration and erection maintenance ability, all three vardenafil doses (5,10 and 20 mg) yielded efficacy rates between 70 and 75%. The most frequently reported side-effects in this trial are summarized in Table 2.
Sildenafil (Viagra™) marked without any doubt a breakthrough in the management of erectile dysfunction and revolutionized the treatment of this disorder. Meanwhile, more than 20 million patients have been treated world-wide with sildenafil, which bears witness to the success of this drug. Despite this impressive success, it is obvious that sildenafil does not have all the features of an ideal impotence drug as, in the long term, 40–50% of all patients discontinue sildenafil medication for various reasons.
It is fair to state that the new PDE-5 inhibitors are, from the perspective of efficacy as measured by questions 3 and 4 of the IIEF or by questions 2 and 3 of the SEP, comparable to sildenafil but differ in terms of pharmacokinetics and intensity of sideeffects.
To date, no data are available from direct head-to-head comparison trials between these three PDE-5 inhibitors, but such trials are under way. There is no question that all three PDE-5 inhibitors are safe and effective, and the future will show us which drug is preferred by couples.
Owing to its low efficacy, compared with the PDE-5 inhibitors, apomorphine sublingual will not play a major role in the future, but its use in so-called psychogenic (functional) erectile dysfunction patients may represent a reasonable alternative. It remains to be seen whether other centrally or peripherally acting drugs may challenge the PDE-5 inhibitors in the future.
Table 2 Results* of the first large phase IIb trial with vardenafil. Data from reference 20