Dapoxetine

Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with an IC₅₀ of 1.12 nM, while its major human metabolites, desmethyldapoxetine (IC₅₀<1.0 nM) and didesmethyldapoxetine (IC₅₀=2.0 nM) are equivalent or less potent (dapoxetine-N-oxide (IC₅₀=282 nM)).

Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculatory pathway originates from a spinal reflex centre, mediated by the brain stem, which is influenced initially by a number of nuclei in the brain (medial preoptic and paraventricular nuclei).

The mechanism of action of dapoxetine in premature ejaculation is presumed to be linked to the inhibition of neuronal reuptake of serotonin and the subsequent potentiation of the neurotransmitter’s action at pre- and postsynaptic receptors.

In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level within the lateral paragigantocellular nucleus (LPGi). Post ganglionic sympathetic fibers that innervate the seminal vesicles, vas deferens, prostate, bulbourethral muscles and bladder neck cause them to contract in a coordinated fashion to achieve ejaculation. Dapoxetine modulates this ejaculatory reflex in rats.

Absorption

Dapoxetine is rapidly absorbed with maximum plasma concentrations (C_max) occurring approximately 1-2 hours after tablet intake. The absolute bioavailability is 42% (range 15-76%), and dose proportional increases in exposure (AUC and C_max) are observed between the 30 and 60 mg dose strengths. Following multiple doses, AUC values for both dapoxetine and the active metabolite desmethyldapoxetine (DED) increase by approximately 50% when compared to single dose AUC values.

Ingestion of a high fat meal modestly reduced the C_max (by 10%) and modestly increased the AUC (by 12%) of dapoxetine and slightly delayed the time for dapoxetine to reach peak concentrations. These changes are not clinically significant. Dapoxetine can be taken with or without food.

Distribution

More than 99% of dapoxetine is bound in vitro to human serum proteins. The active metabolite desmethyldapoxetine (DED) is 98.5% protein bound. Dapoxetine has a mean steady state volume of distribution of 162 L.

Biotransformation

In vitro studies suggest that dapoxetine is cleared by multiple enzyme systems in the liver and kidneys, primarily CYP2D6, CYP3A4, and flavin monooxygenase (FMO1). Following oral dosing of ¹⁴C-dapoxetine, dapoxetine was extensively metabolized to multiple metabolites primarily through the following biotransformational pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation and sulfation. There was evidence of presystemic first-pass metabolism after oral administration.

Intact dapoxetine and dapoxetine-N-oxide were the major circulating moieties in the plasma. In vitro binding and transporter studies show that dapoxetine-N-oxide is inactive. Additional metabolites including desmethyldapoxetine and didesmethyldapoxetine account for less than 3% of the total circulating drug–related materials in plasma. In vitro binding studies indicate that DED is equipotent to dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of dapoxetine. The unbound exposures (AUC and C_max) of DED are approximately 50% and 23%, respectively, of the unbound exposure of dapoxetine.

Elimination

The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged active substance was not detected in the urine. Following oral administration, dapoxetine has an initial (disposition) half-life of approximately 1.5 hours, with plasma levels less than 5% of peak concentrations by 24 hours post-dose, and a terminal half-life of approximately 19 hours. The terminal half-life of DED is approximately 19 hours.

Pharmacokinetics in special populations

The metabolite DED contributes to the pharmacological effect of dapoxetine, particularly when the exposure of DED is increased. Below, in some populations, the increase in active fraction parameters is presented. This is the sum of the unbound exposure of dapoxetine and DED. DED is equipotent to dapoxetine. The estimation assumes equal distribution of DED to the CNS but it is unknown whether this is the case.

Race

Analyses of single dose clinical pharmacology studies using 60 mg dapoxetine indicated no statistically significant differences between Caucasians, Blacks, Hispanics and Asians. A clinical study conducted to compare the pharmacokinetics of dapoxetine in Japanese and Caucasian subjects showed 10% to 20% higher plasma levels (AUC and peak concentration) of dapoxetine in Japanese subjects due to lower body weight. The slightly higher exposure is not expected to have a meaningful clinical effect.

Elderly (age 65 years and over)

Analyses of a single dose clinical pharmacology study using 60 mg dapoxetine showed no significant differences in pharmacokinetic parameters (C_max, AUC_inf, T_max) between healthy elderly males and healthy young adult males. The efficacy and safety has not been established in this population.

Renal impairment

A single-dose clinical pharmacology study using a 60 mg dapoxetine dose was conducted in subjects with mild (CrCL 50 to 80 mL/min), moderate (CrCL 30 to <50 mL/min), and severe renal impairment (CrCL<30 mL/min) and in subjects with normal renal function (CrCL>80 mL/min). No clear trend for an increase in dapoxetine AUC with decreasing renal function was observed. AUC in subjects with severe renal impairment was approximately 2-fold that of subjects with normal renal function, although there are limited data in patients with severe renal impairment. Dapoxetine pharmacokinetics have not been evaluated in patients requiring renal dialysis.

Hepatic impairment

In patients with mild hepatic impairment, unbound C_max of dapoxetine is decreased by 28% and unbound AUC is unchanged. The unbound C_max and AUC of the active fraction (the sum of the unbound exposure of dapoxetine and desmethyldapoxetine) were decreased by 30% and 5%, repectively. In patients with moderate hepatic impairment, unbound C_max of dapoxetine is essentially unchanged (decrease of 3%) and unbound AUC is increased by 66%. The unbound C_max and AUC of the active fraction were essentially unchanged and doubled, respectively.

In patients with severe hepatic impairment, the unbound C_max of dapoxetine was decreased by 42% but the unbound AUC was increased by approximately 223%. The C_max and AUC of the active fraction had similar changes.

CYP2D6 Polymorphism

In a single dose clinical pharmacology study using 60 mg dapoxetine, plasma concentrations in poor metabolizers of CYP2D6 were higher than in extensive metabolizers of CYP2D6 (approximately 31% higher for C_max and 36% higher for AUC_inf of dapoxetine and 98% higher for C_max and 161% higher for AUC_inf of desmethyldapoxetine). The active fraction of dapoxetine may be increased by approximately 46% at C_max and by approximately 90% at AUC. This increase may result in a higher incidence and severity of dose dependent adverse events. The safety of dapoxetine in poor metabolizers of CYP2D6 is of particular concern with concomitant administration of other medicinal products that may inhibit the metabolism of dapoxetine such as moderate and potent CYP3A4 inhibitors.

A full assessment of the safety pharmacology, repeat dose toxicology, genetic toxicology, carcinogenicity, dependence/withdrawal liability, phototoxicity and developmental reproductive toxicology of dapoxetine was conducted in preclinical species (mouse, rat, rabbit, dog and monkey) up to the maximum tolerated doses in each species. Due to the more rapid bioconversion in the preclinical species than in man, pharmacokinetic exposure indices (C_max and AUC_0-24hr) at the maximum tolerated doses in some studies approached those observed in man. However, the body weight normalized dose multiples were greater than 100-fold. There were no clinically relevant safety hazards identified in any of these studies.

In studies with oral administration, dapoxetine was not carcinogenic to rats when administered daily for approximately two years at doses up to 225 mg/kg/day, yielding approximately twice the exposures (AUC) seen in human males given the Maximum Recommended Human Dose (MRHD) of 60 mg. Dapoxetine also did not cause tumors in Tg.rasH2 mice when administered at the maximum possible doses of 100 mg/kg for 6 months and 200 mg/kg for 4 months. The steady state exposures of dapoxetine in mice following 6-months oral administration at 100 mg/kg/day were less than the single dose exposures observed clinically at 60 mg.

There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats and no adverse signs of embryotoxicity or fetotoxicity in the rat or rabbit. Reproductive toxicity studies did not include studies to assess the risk of adverse effects after exposure during the peri-post-natal period.