Dapoxetine, a novel selective serotonin transport inhibitor for the treatment of premature ejaculation
CLINICAL EVIDENCE
Dapoxetine
Although SSRIs are intended for chronic use in the treatment of depression and are designed to have pharmacokinetic profiles that would allow them to provide constant systemic concentration with long-term administration, they may need days to weeks to reach a maximum steady-state concentration in order to exhibit efficacy (Hiemke and Hartter 2000). Therefore, SSRIs are commonly used in a daily dosing schedule for the treatment of PE (Montague et al 2004). In addition to the potentially desirable side-effect of delaying ejaculation, this dosing regimen for long-acting SSRIs is associated with a number of undesirable side-effects, such as decreased libido and ED (Montague et al 2004). With the success of daily SSRI use in delaying ejaculation, it has been suggested that on-demand treatment with SSRIs possessing a short half-life and short Tmax would be equally effective, more convenient, and exhibit fewer serotonergic side-effects than observed with daily treatment (Waldinger 2005). Therefore, an ideal compound for the treatment of PE should exhibit pharmacokinetic profiles having rapid absorption, adequate availability to establish therapeutic exposure at the target site, and rapid elimination to reduce total drug exposure and minimize the incidence of side-effects (Modi et al 2006).
Dapoxetine, ((+)-(S)-N,N-dimethyl-(a)-[2-(1-naphthalenyloxy)ethyl]-benzenemethanamine hydrochloride) is a novel potent serotonin transport inhibitor with a unique pharmacokinetic profile, and is currently in development for use in the treatment of PE (Dresser et al 2004; Gengo et al 2005). Dapoxetine hydrochloride is a water-soluble powder with a molecular weight of 341.88 and has a pKa of 8.6 and is mainly charged at a physiological pH. These pharmacological characteristics allow for rapid distribution in the body and are different from the pharmacokinetics observed in conventional SSRIs. Dapoxetine is a fast-acting compound that attains its peak plasma concentration in about 1.5 hours after dosing, which is much faster than fluoxetine, paroxetine, or sertraline (Strassberg et al 1999, 2005; Eli Lilly 2005; GlaxoSmithKline 2005; Pfizer 2005). After oral administration, dapoxetine is readily absorbed, followed by a rapid decline in plasma concentrations. These pharmacokinetic properties make dapoxetine an excellent candidate for on-demand dosing, which avoids the potential disadvantages of continuous pharmacotherapy. The pharmacokinetic characteristics of dapoxetine compared with paroxetine and sertraline are provided in Table 2.
Table 2
Pharmacokinetic characteristics of dapoxetine compared with paroxetine and sertraline
Although the pharmacological action of dapoxetine is similar to that of clomipramine and conventional SSRIs, the chemical structure and pharmacokinetic profile of dapoxetine differentiates it from other SSRIs. Dapoxetine is not a halogenated compound, whereas others contain one or more halogen atoms. The molecular structure of dapoxetine also includes a naphthyl moiety and it is possible that these features underpin the physicochemical and pharmacokinetic properties of the molecule.
Dapoxetine is a potent inhibitor of the 5-HT reuptake transporter. Studies conducted in cells expressing the human transcript of the 5-HT, norepineprine, and dopamine reuptake reporters to determine the inhibition constant (Ki) and the activity of dapoxetine (IC50) values showed that dapoxetine competed in a concentration-dependent manner for specific [3H]citalopram binding sites on the 5-HT reuptake transporter (Ki = 9.5), specific [3H]nisoxatine binding sites on the norepinephrine reuptake transporter (Ki = 6.6), and specific [3H]WIN35428 binding sites on the dopamine reuptake transporter (Ki = 5.8) (Gengo et al 2005). Additionally, dapoxetine inhibited the uptake of [3H]5-HT by the 5-HT reuptake transporter with a value of 1.12 nM, whereas the uptake of [3H]norepinephrine into cells utilizing the norepinephrine reuptake transporter and uptake of [3H]dopamine by the dopamine reuptake transporter were inhibited by dapoxetine with IC50 values of 202 nM and 1720 nM, respectively. In conclusion, dapoxetine binds to 5-HT, norepinephrine, and dopamine reuptake transporters and inhibits 5-HT, norepinephrine, and dopamine uptake with an order of potency: 5-HT > norepinephrine dopamine.
A double-blind, randomized, placebo-controlled, crossover, 3-period phase II US study of dapoxetine for the treatment of PE, comparing the safety and efficacy of on-demand dapoxetine 60 mg versus 100 mg versus placebo was presented (Hellstrom 2004). Each of the three 2-week treatment periods was separated by a 72-hour washout period. The patients enrolled in the study were all heterosexual men aged 18–65 years who had been involved in a stable, monogamous relationship for at least 6 months and whose baseline IELT was under 2 minutes, as measured by the partner using a stopwatch. The primary endpoint was IELT, as well as patients’ satisfaction control over ejaculation. A total of 130 men with PE completed the study. The mean baseline IELT increased from 1.01 minutes to 2.94 minutes with 60 mg dapoxetine, 3.20 minutes with 100 mg dapoxetine, and 2.05 minutes with placebo (p < 0.0001 vs placebo). Patients who received the 60-mg dose of dapoxetine reported significant increases in their control over ejaculation from baseline (p < 0.0001) and significant benefits in their sexual satisfaction (with their sexual intercourse episodes). Nausea, the most common reported adverse effect, occurred in 5.6% of patients who received 60 mg, 16.1% of those who received 100 mg, and 0.7% of those who received placebo (Table 3) (Hellstrom 2004). Of the 10 patients who discontinued the study because of side-effects, 9 were receiving the 100-mg dose of dapoxetine and 1 patient was receiving placebo.
Table 3
Adverse events observed with dapoxetine (60 mg and 100 mg) and placebo
Another two phase II clinical trials investigated the efficacy and tolerability of 20, 40, 60, and 100 mg dapoxetine in order to determine the appropriate on-demand doses of dapoxetine for further study in large-scale phase III clinical trials (Hellstrom et al 2005). Both double-blind, multi-center, randomized, placebo-controlled, 3-period cross-over phase II studies enrolled men with PE, based on DSM-IV-TR criteria and IELT. Subjects were instructed to take study drug prior to the anticipated sexual intercourse (1–3 hours prior in study 1, and 1–2 hours prior in study 2) and to attempt sexual intercourse ≥ twice weekly. The primary endpoint was IELT measured with a stopwatch held by the female partner. In study 1, 128 of 157 patients (20 mg and 40 mg dapoxetine), and in study 2, 130 of 166 (60 mg and 100 mg dapoxetine) randomized subjects completed the trials. All four doses of dapoxetine documented statistically significant improvements in IELT over placebo (Table 4).
Table 4
The efficacy of various doses of dapoxetine on IELT
In a recent study by Pryor et al (2005), the efficacy and tolerability of dapoxetine in the treatment of PE were evaluated. Men with PE (n = 2614) as defined by DSM-IV-TR criteria were enrolled in 2 randomized, double-blind, placebo-controlled, multi-center, phase III clinical trials of identical design, and each had a 2-week baseline period and 12-week treatment period. At the end of the baseline period, subjects with mean IELT ≥ 2 minutes were randomized 1:1:1 to placebo, dapoxetine 30 mg, or 60 mg, and instructed to take the study drug 1–3 hours prior to anticipated sexual intercourse. The primary efficacy endpoint was IELT adjusted for baseline, as measured by a stopwatch held by the female partner. Secondary endpoints were subjective perception of Control Over Ejaculation and Satisfaction With Sexual Intercourse, and were assessed at baseline, 4, 8, and 12 weeks, and rated on 5-point scales of between 0 (very poor) and 4 (very good). Preliminary results of this study demonstrated that there were significant differences between placebo and each active treatment group in mean IELT, Control Over Ejaculation, and Satisfaction With Sexual Intercourse (p < 0.0001). Changes from baseline to study end point for mean IELT were 0.90–1.75 min (placebo), 0.92–2.78 minutes (30 mg dapoxetine), and 0.91–3.32 minutes (60 mg dapoxetine). Both dapoxetine 30 mg and 60 were found to be more effective than placebo in increasing IELT on first dose. Treatment-related side-effects (incidence ≥5%) with both 30 mg and 60 mg dapoxetine were nausea (8.7% and 20.1%), headache (5.9% and 6.8%), diarrhea (6.8% with 60 mg), and dizziness (6.2% with 60 mg). Discontinuation rates due to adverse effect were reported as 0.0%, 4%, and 10% for placebo, 30 mg, and 60 mg doses of dapoxetine, respectively. The authors concluded that dapoxetine 30 mg or 60 mg is effective for the on-demand treatment of PE, with increased IELT, improved Control Over Ejaculation, and increased Satisfaction With Sexual Intercourse.
The use of ethanol and PDE-5 inhibitors with sexual activity is recognized. The interactions of dapoxetine with PDE-5 inhibitors and ethanol have also been investigated. The effects of PDE-5 inhibitors on the pharmacokinetics of dapoxetine were studied in a randomized, open-label, 3-period crossover study in healthy male subjects (n = 24; 18–45 years of age) receiving a single 60-mg dose of dapoxetine, dapoxetine 60 mg plus sildenafil 100 mg, and dapoxetine 60 mg plus tadalafil 20 mg (Dresser et al 2006). Each treatment was separated by a 6- to 14-day washout period. Blood samples were collected predose and at specified times after dosing for measurement of dapoxetine and its metabolites and tadalafil and sildenafil plasma concentrations. This study demonstrated that sildenafil and tadalafil did not have a clinically significant effect on the pharmacokinetics of dapoxetine. In the other study that was designed as double-blind, randomized, and 4-period crossover in healthy male adult subjects, the effect of ethanol on the pharmacokinetics of dapoxetine was investigated (Modi et al 2005). Each separate treatment period of a single dose of dapoxetine 60 mg and a single dose of 0.5 g/kg ethanol, dapoxetine 60 mg and ginger ale (placebo for ethanol), placebo (for dapoxetine) and 0.5 g/kg ethanol, and placebo for both drugs was administered with a 5- to 21-day washout period. Safety was assessed by adverse event reporting throughout the study and by laboratory tests, and blood samples were collected predose and at specified times after for measurement of plasma concentrations of dapoxetine and its metabolites and ethanol analysis. The results of this study demonstrated that co-administration of ethanol with dapoxetine did not produce significant changes in dapoxetine pharmacokinetics.
Go to:
Conclusions
Neurobiological studies in animals and humans have provided better understanding of the physiology of ejaculation and pathophysiology of PE. The nature of PE is such that patients should not have to chronically take potent psychoactive drugs, with long-lasting actions and debilitating side-ef-fects. Dapoxetine is a selective serotonin transport inhibitor with unique pharmacokinetic and pharmocodynamic properties that account for its clinical effects. Future studies may demonstrate whether dapoxetine could possess many of the attributes of an ideal compound for the treatment of PE.
Please Scroll Down to See Forums Below 
We can all admit in the nicest possible way it is a nice feeling when they can't walk so good afterwards 
