Treatment of Premature Ejaculation with Dapoxetine

Fig. 20.1

Molecular structure of dapoxetine: (+)-(S)-N,N-dimethyl-(α)-[2(1naphthalenyloxy)ethyl]-benzenemethanamine hydrochloride

20.3.1 Pharmacokinetics and Metabolism

Dapoxetine undergoes rapid absorption and elimination resulting in minimal accumulation and has dose-proportional pharmacokinetics, which are unaffected by multiple dosing and do not vary between ethnic groups (Fig. 20.2) [34–36]. The pharmacokinetic profile of dapoxetine suggests that it is a good candidate for on-demand treatment of PE.

Fig. 20.2

Plasma concentration profiles of dapoxetine after administration of a single dose or multiple doses of dapoxetine 30 mg (a) and dapoxetine 60 mg (b) [36]

The pharmacokinetics of both single doses and multiple doses over 6–9 days (30, 60, 100, 140, or 160 mg) of dapoxetine have been evaluated. In a randomized, double-blind, placebo-controlled trial, single doses and multiple doses over 6 days of dapoxetine (60, 100, 140, or 160 mg) were administered to 77 healthy male volunteers [34, 35, 37]. Dapoxetine has a T _max of 1.4–2.0 h and rapidly achieves peak plasma concentration (C _max) following oral administration. Both plasma concentration and area under the curve (AUC) are dose dependent up to 100 mg. The mean half-life of dapoxetine after a single dose was estimated using modeling as 1.3–1.5 h. Dapoxetine plasma concentrations rapidly decline to about 5 % of C _max at 24 h. The terminal half-life of dapoxetine was 15–19 h after a single dose and 20–24 h after multiple doses of 30 and 60 mg, respectively.

In a second pharmacokinetic study, single doses and multiple doses of dapoxetine (30, 60 mg) were evaluated in a randomized, open-label, 2–treatment, 2-period, crossover study of 42 healthy male volunteers over 9 days [36]. Subjects received a single dose of dapoxetine 30 mg or 60 mg on day 1 (single-dose phase) and on days 4–9 (multiple-dose phase). Dapoxetine was rapidly absorbed, with mean maximal plasma concentrations of 297 and 498 ng/ml at 1.01 and 1.27 h after single doses of dapoxetine 30 and 60 mg, respectively (Table 20.1). Elimination of dapoxetine was rapid and biphasic, with an initial half-life of 1.31 and 1.42 h, and a terminal half-life of 18.7 and 21.9 h following single doses of dapoxetine 30 and 60 mg, respectively. The pharmacokinetics of dapoxetine and its metabolites were not affected by repeated daily dosing and steady state plasma concentrations were reached within 4 days, with only modest accumulation of dapoxetine (approx. 1.5-fold) (Fig. 20.2b).

Table 20.1

Pharmacokinetics of single doses of dapoxetine (30, 60 mg) and effect of food on pharmacokinetics [34]

	Dapoxetine 30 mg	Dapoxetine 60 mg
C _max(ng/ml)	297	349
T _max (hr)	1.01	1.27
Initial T ^1/2 (h)	1.31	1.42
Terminal T ^1/2 (hr)	18.7	21.0
Effect of High Fat Meal
C _max(fasted)	–	443
C _max (high fat meal)	–	398
T _max(hr) (fasted)	–	1.30
T _max (hr) (high fat meal)	–	1.83

Food does not have a clinically significant effect on dapoxetine pharmacokinetics. Mean maximal plasma concentrations of dapoxetine decrease slightly after a high-fat meal, from 443 ng/ml (fasted) to 398 ng/ml (fed), and are delayed by approx. 0.5 h following a high-fat meal (1.30 h fasted, 1.83 h fed) [35]. The rate of absorption is modestly decreased, but there is no effect of food on the elimination of dapoxetine or the exposure to dapoxetine, as assessed by the area under the plasma concentration vs. time curve (AUC). The frequency of nausea is decreased after a high-fat meal (24 % [7/29] of fasted subjects and 14 % [4/29] of fed subjects, respectively).

Dapoxetine is extensively metabolized in the liver by multiple isozymes to multiple metabolites, including desmethyldapoxetine, didesmethyldapoxetine and dapoxetine-n-oxide, which are eliminated primarily in the urine [34, 36]. Although didesmethyldapoxetine is equipotent to the parent dapoxetine, its substantially lower plasma concentration, compared with dapoxetine, limits its pharmacological activity and it exerts little clinical effect, except when dapoxetine is coadministered with CYP3A4 or CYP2D6 inhibitors.

20.3.2 Animal Studies

Animal studies using rat experimental models have demonstrated that acute treatment with oral, subcutaneous, and IV dapoxetine inhibits ejaculation at doses as low as 1 mg/kg. Dapoxetine appears to inhibit the ejaculatory reflex at a supraspinal level with the lateral paragigantocellular nucleus (LPGi) as a necessary brain structure for this effect [38].

Clement et al. reported the effects of IV dapoxetine on the emission and ejection phases of ejaculation using p-chloroamphetamine (PCA)-induced ejaculation as an experimental model of ejaculation in anesthetized rats [39]. Intraseminal vesicle pressure and electromyograms of bulbospongiosus muscles were used as physiologic markers of the emission and ejection phases, respectively. At all doses, dapoxetine significantly reduced the proportion of rats displaying PCA-induced ejaculation in a dose-dependent manner, from 78 % of rats with vehicle to 33, 22, and 13 % of rats following IV dapoxetine 1, 3, and 10 mg/kg, respectively. Dapoxetine significantly decreased the AUC of PCA-induced intraseminal vesicle pressure increases and bulbospongiosus muscle contractile bursts by 78 % at all doses, and by 91 % following dapoxetine 1 and 10 mg/kg and by 85 % following dapoxetine 3 mg/kg.

Using a different animal experimental model of the ejaculatory reflex in rats, Giuliano et al. measured the latency, amplitude and duration of pudendal motoneuron reflex discharges (PMRD) elicited by stimulation of the dorsal nerve of the penis before and after IV injection of vehicle, dapoxetine or paroxetine (1, 3, and 10 mg/kg) [40]. At the three doses of dapoxetine tested, the latency of PMRD following stimulation of the dorsal nerve of the penis was significantly increased and the amplitude and duration of PMRD decreased from baseline values. Acute IV paroxetine appeared less effective than dapoxetine.

In a behavioral study of sexually experienced rats, Gengo et al. reported that treatment with subcutaneous or oral dapoxetine significantly delayed ejaculation compared to saline control (16 ± 4 min with subcut. versus 10 ± 1 min in saline controls, p < 0.05) when administered 15, but not 60 or 180 min prior to exposure to receptive females [41]. The greatest delay in ejaculatory latency was observed in animals with shorter baseline latencies and oral dapoxetine did not affect the latency in rats with a baseline latency longer than 10 min.

20.3.3 Clinical Efficacy

The results of two phase 2 and five phase 3 trials have been published [42–47].

20.3.3.1 Phase 2 Trials

Dapoxetine dose-finding data has been derived from two multicenter phase 2 studies and used to determine the appropriate doses for phase 3 studies. Both studies used a randomized, placebo-controlled, double-blind, 3-period, crossover study design and subjects with PE diagnosed according to DSM-IV criteria and a baseline IELT <2 min on 75 % of ≥4 sexual intercourse events. Study drug was administered 1–2 h prior to planned sexual intercourse and subjects were required to attempt intercourse at least twice a week. The primary outcome measure was the partner-operated stopwatch IELT.

In study 1, 128/157 randomized subjects completed the study [43]. Subjects were randomized to receive dapoxetine 20 mg, dapoxetine 40 mg, or placebo for 4 weeks with no washout period between treatment arms. Baseline IELT (mean baseline IELT = 1.34 min.) was estimated by patient recall. In study 2, 130/166 randomized subjects completed the study [42]. Subjects were randomized to receive dapoxetine 60 mg, dapoxetine 100 mg, or placebo for 2 weeks, separated by a 3 day washout period. Baseline IELT (mean baseline IELT = 1.01 min.) was measured by partner operated stopwatch.

The intention-to-treat analysis of both studies demonstrated that all four doses of dapoxetine are effective, superior to placebo and increased IELT 2.0–3.2-fold over baseline in a dose-dependent fashion (Table 20.2) [42, 43]. The magnitude of effect of dapoxetine 20 mg on IELT was small. The most commonly reported adverse events (AEs) were nausea, diarrhoea, headache, dizziness. The incidence of most AEs appeared to be dose-dependent. The most common adverse event was nausea and occurred in 0.7, 5.6, and 16.1 % of subjects with placebo, dapoxetine 60 mg and dapoxetine 100 mg, respectively. Overall, dapoxetine 60 mg was better tolerated than dapoxetine 100 mg. Based on these results, doses of 30 mg and 60 mg were chosen for further investigation in phase 3 efficacy and safety studies.

Table 20.2

Results of dapoxetine phase 2 and 3 studies [42]

	Phase- 2 studies						Phase- 3 studies (pooled)
	Study 1			Study 2			Study 1–5
Age range (years)	18–60			18–65			18–82
Inclusion criteria, IELT	DSM-IV TR, <2 min estimated			DSM-IV TR, <2 min by stopwatch			DSM-IV TR, <2 min by stopwatch
Number (subjects)	157			166			6,081
Treatment (period)	4 weeks per treatment			2 weeks per treatment			9–24 weeks, parallel, fixed dose
Washout (period)	None			72 h			None
Dapoxetine dose	20 mg (n = 145)	40 mg (n = 141)	Placebo (n = 142)	60 mg (n = 144)	100 mg (n = 155)	Placebo (n = 145)	30 mg (n = 1,613)	60 mg (n = 1,611)	Placebo (n = 1,608)
Mean baseline IELT	1.34	1.34	1.34	1.01	1.01	1.01	0.9	0.9	0.9
Mean treatment IELT	2.72^*	3.31^†	2.22	2.86^†	3.24^†	2.07	3.1^†	3.6^†	1.9
IELT fold increase	2.0	2.5	1.7	2.9	3.2	2.0	2.5	3.0	1.6
“Good/very good” control
Baseline (%)	–	–	–	–	–	–	0.3	0.6	0.5
Study end (%)	–	–	–	–	–	–	11.2^†	26.2^†	30.2
“Good/very good” satisfaction
Baseline (%)	–	–	–	–	–	–	15.5	14.7	15.5
Study end (%)	–	–	–	–	–	–	24.4^†	37.9^†	42.8
“Quite a bit/extreme” personal distress
Baseline (%)	–	–	–	–	–	–	73.5	71.3	69.7
Study end (%)	–	–	–	–	–	–	41.9^†	28.2^†	22.2
“Quite a bit/extreme” interpersonal distress
Baseline (%)	–	–	–	–	–	–	38.5	38.8	36.1
Study end (%)	–	–	–	–	–	–	23.8^†	6.0^†	12.3
Discontinuation due to AE	0	2	0	0	9	1	3.5	8.8	1.0

^*p = 0.042, ^†p < 0.0001 vs. placebo

20.3.3.2 Phase 3 Trials

The five randomized, placebo-controlled, phase 3 clinical trials comprised two identically designed studies conducted in the United States [44], an international study conducted in 16 countries in Europe, Argentina, Brazil, Canada, Israel, Mexico, and South Africa [45], a North American safety study [46], and an Australian and Asia–Pacific country study [47]. The treatment period ranged from 9–24 weeks. Overall, 6,081 men with a mean age of 40.6 years (range, 18–82 years) from 32 countries were enrolled with 4,232 (69.6 %) subjects completing their study (Table 20.2). This is the largest efficacy and safety database for any agent intended to treat PE.

The DSM-IV-TR criteria and a baseline IELT <2 min on 75 % of ≥4 sexual intercourse events were used to enroll subjects in four of the five phase 3 studies [44, 45, 47]. Baseline average IELT was 0.9 min for subjects overall. However, 58 % of subjects also met the ISSM criteria for lifelong PE [48]. Subjects reported having had PE for an average of 15.1 years, with 64.9 % of subjects classified by the investigator as having lifelong PE at screening. Demographic and baseline characteristics were similar across studies allowing an analysis of pooled phase 3 data.

Outcome measures included stopwatch IELT, the premature ejaculation profile (PEP), a validated tool that includes measures of perceived control over ejaculation, satisfaction with sexual intercourse, ejaculation-related personal distress, ejaculation-related interpersonal difficulty [49], and subject response to a multidimensional clinical global impression of change (CGIC) in PE question: “Compared to the start of the study, would you describe your PE problem as much worse, worse, slightly worse, no change, slightly better, better, or much better?”

An analysis of pooled phase 3 data confirms that dapoxetine 30 and 60 mg increased IELT and improved patient reported outcomes (PROs) of control, ejaculation-related distress, interpersonal distress and sexual satisfaction, compared to placebo. Efficacy results were similar among each of the individual trials and for a pooled analysis, indicating that dapoxetine is consistently more efficacious than placebo regardless of a subject’s demographic characteristics.

Increases in mean average IELT (Table 20.2) were significantly greater with both doses of dapoxetine vs. placebo beginning with the first dose of study medication (dapoxetine 30 mg, 2.3 min; dapoxetine 60 mg, 2.7 min; placebo, 1.5 min; p < 0.001 for both) and at all subsequent time points (all p <0.001). By week 12, mean average IELT had increased to 3.1 and 3.6 min. with dapoxetine 30 and 60 mg, respectively (versus 1.9 min. with placebo; p < 0.001 for both; Table 20.2).

However, as IELT in subjects with PE is distributed in a positively skewed pattern, reporting IELTs as arithmetic means may overestimate the treatment response and the geometric mean IELT is more representative of the actual treatment effect [50]. Geometric mean average IELT increased from approx. 0.8 min at baseline to 2.0 and 2.3 min with dapoxetine 30 and 60 mg, respectively (vs. 1.3 min with placebo; p < 0.001 for both). Furthermore, as subjects have a broad range of baseline IELT values (0–120 s), reporting mean raw trial-end IELT may be misleading by incorrectly suggesting all subjects respond to that extent. The trial-end fold increase in geometric mean IELT compared to baseline is more representative of true treatment outcome and must be regarded as the contemporary universal standard for reporting IELT. Geometric mean IELT fold increases of 2.5 and 3.0 were observed with dapoxetine 30 and 60 mg, respectively, vs. 1.6 for placebo ( p < 0.0001 for both, Table 20.2). Fold increases were greater among men with very short baseline IELT values, suggesting that dapoxetine may be a useful treatment option for men with severe forms of PE, including anteportal ejaculation. Subjects with baseline average IELTs of 0.5–1.0 min, and ≤0.5 min showed fold increases of 2.4 and 3.4, respectively, with dapoxetine 30 mg, and 3.0 and 4.3 with dapoxetine 60 mg compared to 1.6 and 1.7, respectively, with placebo treatment.

Control over ejaculation was reported as “good” or “very good” by <1.0 % of subjects at baseline and improved to 26.2 % and 30.2 % with dapoxetine 30 and 60 mg, respectively, vs. 11.2 % with placebo by week 12 (p < 0.001 for both; Table 20.2). Approximately 15 % of subjects reported “good” or “very good” satisfaction with sexual intercourse at baseline; by week 12, this increased to 37.9 % and 42.8 % with dapoxetine 30 and 60 mg, respectively, versus 24.4 % with placebo (p < 0.001 for both; Table 20.2). While approx. 70 % of subjects across groups reported “quite a bit” or “extremely” for their level of ejaculation-related personal distress at baseline, by week 12 this decreased to 28.2 % and 22.2 % with dapoxetine 30 and 60 mg, respectively, vs. 41.9 % with placebo ( p < 0.001 for both; Table 20.2). Approximately one-third of subjects reported “quite a bit” or “extremely” for their level of ejaculation-related interpersonal difficulty at baseline; by week 12 this decreased to 16.0 % and 12.3 % with dapoxetine 30 and 60 mg, respectively, vs. 23.8 % with placebo ( p < 0.001 for both; Table 20.2).

A significantly greater percentage of subjects reported that their PE was “better” or “much better” at week 12 with dapoxetine 30 (30.7 %) and 60 mg (38.3 %) than with placebo (13.9 %; p < 0.001 for both). Similarly, 62.1 % and 71.7 % of subjects reported that their PE was at least “slightly better” at week 12 with dapoxetine 30 and 60 mg, respectively, compared to 36.0 % with placebo ( p < 0.001 for both).

Several studies have reported that the effects of PE on the partner are integral to understanding the impact of PE on the male and on the sexual relationship [9, 51–53]. If PE is to be regarded as a disorder that affects both subjects and their partners, partner PROs must be regarded as important measures in determining PE severity and treatment outcomes. Female partners reported their perception of the man’s control over ejaculation and CGIC, their own satisfaction with sexual intercourse, interpersonal difficulty and personal distress. A significantly greater percentage of female partners reported that the man’s control over ejaculation was “good” or “very good” with dapoxetine 30 (26.7 %) and 60 mg (34.3 %) vs. placebo at week 12 (11.9 %; p < 0.0001 for both). Similarly, a significantly greater percentage of female partners reported that the man’s PE was at least “better” with dapoxetine 30 (27.5 %) and 60 mg (35.7 %) vs. placebo (9.0 %; p < 0.001 for both). A greater percentage of female partners reported that their own satisfaction with sexual intercourse was “good” or “very good” with dapoxetine 30 (37.5 %) and 60 mg (44.7 %) vs. placebo (24.0 %; p < 0.001 for both). Finally, there were significant decreases in both ejaculation-related personal distress and interpersonal difficulty in female partners of men treated with dapoxetine 30 and 60 mg vs. placebo (p < 0.001 for both) [45].

20.4 Safety and Tolerability

Across trials, dapoxetine 30 and 60 mg were well tolerated with a low incidence of severe AEs. More than 50 % of all phase 3 AEs were reported at the first follow-up visit after 4 weeks of treatment and typically included gastrointestinal and central nervous system symptoms. The most frequently reported AEs were nausea, diarrhea, headache, dizziness, insomnia, somnolence, fatigue, and nasopharyngitis (Table 20.3). Unlike other SSRIs used to treat depression, which have been associated with high incidences of sexual dysfunction, [54, 55] dapoxetine was associated with low rates of sexual dysfunction. The most common AE in this category was ED (placebo, 1.6 %; dapoxetine 30 mg prn, 2.3 %; dapoxetine 60 mg prn, 2.6 %; dapoxetine 60 mg qd; 1.2 %). AEs were dose-dependent and generally coincided with the pharmacokinetic profile of dapoxetine, occurring at the approximate time of peak serum concentrations [~1.3 h] and lasting for approx. 1.5 h. Most AEs were mild to moderate in severity, and few subjects across groups reported severe (~3 %) or serious (≤1 %) AEs. Adverse effects led to the discontinuation of 1.0, 3.5, 8.8, and 10.0 % of subjects with placebo, dapoxetine 30 mg prn, dapoxetine 60 mg prn, and dapoxetine 60 mg qd, respectively.

Table 20.3

Treatment-emergent adverse events occurring in ≥2 % of subjects in pooled phase 3 data [44]