Volume 50, Issue 5, Pages 901-902 (November 2006)
Article Outline:
The time we spend with a patient explaining how to use a phosphodiesterase type 5 inhibitor (PDE5-I) and the quality of the information we provide are recognised as important factors that contribute to the success of the treatment.
Several investigators have already reported that by simply reviewing “use instructions” with patients in whom PDE5-I therapy has failed, a significant percentage of them become responders. Thus, publications such as the one by Porst et al. [1] that appears in this issue of the journal should provide useful clinical information.
On-demand use of PDE5-Is, regardless of which PDE5-I, necessarily requires planning on the part of the patients. Physicians must know what the therapeutic window for each PDE5-I is, that is, when its onset of action is and how long the effect will last. Other confounding factors that may influence efficacy, such as food, and what type of food, in the stomach at the time of PDE5-I intake, must be considered, particularly if the therapeutic window is short.
Pharmacokinetic studies evaluate the fate of a molecule introduced into the body and provide useful information that helps predict onset of action and duration of effect of that molecule. One of the parameters measured that helps predict the duration of action of a molecule is its plasma half-life (t1/2). The half-life in plasma of a molecule is defined as the time, typically in hours, required to reduce by 50% the maximal concentration reached in plasma (IC50) after oral administration of a molecule. Klotz et al. [2] reported a half-life for vardenafil of 4.7h, a little longer than that reported for sildenafil (approximately 4h) and shorter than the 17.5h reported for tadalafil. One would then expect that after 5–6h vardenafil would have a significant decay in efficacy if half-life were the key, or the only, parameter influencing the duration of effect.
Retrospective analysis of pooled data from several clinical trials showed that patients were able to obtain and maintain an erection until successful completion of intercourse (Sexual Encounter Profile [SEP], question 3) 8–12h after taking vardenafil [3]. This justified performing the prospective study published in this issue of the journal.
In this study, patients were asked to take the medication and engage in intercourse 8h later. A ±2-h window was included in the analysis because patients tend to deviate, to some degree, from the protocol. Thus, the reported data provide information on the efficacy of vardenafil up to 10h after its administration. In my opinion, Fig. 3A and B provide the key data of this paper. Not only is there significant efficacy between 9 and 10h after drug intake but this efficacy is not different from that in the 6–7h after treatment. This suggests sustained efficacy for a therapeutic window of up to 10h. This is critical information for patients.
Why then does a drug with a half-life of 4.8h have sustained efficacy for at least 10h? A possible explanation comes from the high biochemical potency of vardenafil. Blount et al. [4] reported an IC50 of 0.09nM. Under the same assay conditions, sildenafil and tadalafil were 40 and 20 times, respectively, less potent than vardenafil.
This high potency means that vardenafil has very high affinity for its binding site on the PDE5 molecule, the so-called catalytic binding site. It is at this site in the enzyme that PDE5-Is bind, displacing cyclic guanosine monophosphate and thus preventing it hydrolysis. Blount et al. [4] have also reported that once vardenafil is bound to PDE5 its “off-rate” or detachment of the PDE5-vardenafil complex is very slow compared to that of tadalafil or sildenafil. So when vardenafil enters the cell and reaches its target, it is “sequestered” in the cell because of its high affinity binding to PDE5. It would be possible then to have low plasma levels of vardenafil while the drug is attached to its target in the cell. This may explain, at least in part, the apparent discrepancy between plasma half-life and duration of efficacy reported by Porst et al. [1].
References
1. Porst H, Sharlip ID, Hatzichristou D, et al.. Extended duration of efficacy of vardenafil when taken 8 hours before intercourse: a randomized, double-blind, placebo-controlled study. Eur Urol. 2006;50:1086–1095.
2. Klotz T, Bauer R-J, Rohde G. Effect of renal impairment on the single-dose pharmacokinetics of vardenafil 20mg, a selective PDE5 inhibitor for the treatment of erectile dysfunction. Pharmacotherapy. 2002;22:418.
3. Valiquette L, Montorsi F, Hellstrom WJVardenafil Study Group. Penetration and maintenance of erection with vardenafil: a time-from-dosing analysis. Can J Urol. 2005;12:2687–2698.
4. Blount MA, Beasley A, Zoraghi R, et al.. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol. 2004;66:144–152.
Iñigo Sáenz de Tejada
Instituto de Medicina Sexual, Madrid, Spain
published online 10 August 2006.Please log-in or register in order to submit comments. Powered by AkoComment! |
Erectile Dysfunction (ED) 
