EVER LONG TABLET

Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and phosphodiesterase-5 tadalafil and sildenafil inhibitors, agents used in the treatment of erectile dysfunction (ED), were investigated in an open label, randomized crossover study (n = 24 men ) comparing ever long tablet 60 mg, dapoxetine 60 mg + tadalafil 20 mg and dapoxetine 60 mg + sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, while sildenafil increased dapoxetine AUCinf by 22%; these effects were not considered clinically significant. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most side effects were mild. Therefore, dapoxetine has no clinically significant pharmacokinetic interactions with tadalafil or sildenafil, and the combination is well tolerated.

Introduction

Premature ejaculation (PE) is a common form of male sexual dysfunction, which has been shown to cause significant harm to men and their partners.1,2,3 Although non-intended to treat PE, a conventional selective serotonin reuptake inhibitor (SSRI), antidepressants are commonly used to treat this disease.

A new serotonin transporter inhibitor, dapoxetine, was specifically developed for PE.7 treatment. Results from placebo-controlled randomized, multicenter Phase III studies demonstrated that males with PE using dapoxetine 30 or 60 mg experienced increased intravaginal ejaculatory latency and higher levels of control over ejaculation and satisfaction by sex. Dapoxetine was effective on on-demand administration 1-3 hours before sexual intercourse. In contrast, large (N> 100) efficacy and safety studies in men with PE with conventional SSRI antidepressants have not been performed and studies of these agents for the treatment of PE were rarely controlled by placebo.

A significant proportion of PE males also have erectile dysfunction (ED). 8, 9 While some studies have evaluated the efficacy of ED treatment in men with comorbid PE and ED, 10, 11 very few have examined the prevalence of these comorbid conditions. A large survey, which included 12,134 men from the United States, Germany and Italy, recently found that 7.2% of men met the criteria for both PE and ED12. A total of 32% of men with PE also reported ED while 44% of ED men also reported PE.

Because of a significant proportion of PE and ED men, phosphodiesterase (PDE) -5 inhibitors including tadalafil (CIALIS®, Lilly ICOS, LLC, Indianapolis, IN, USA) or sildenafil (VIAGRA®, Pfizer Inc., New York, USA) can be expected in patients receiving dapoxetine.9 As such, PDE-5 inhibitors are likely to be a common concomitant drug and the potential for drug interactions with Ever long tablet in Pakistan  should be evaluated.

Dapoxetine is extensively metabolised to multiple Phase I and Phase II metabolites by more cytochrome P450 isoforms (CYP), with no predominant enzyme (unpublished data) being predominant. Since there are several parallel routes of dapoxetine metabolism, significant metabolic pharmacokinetic interactions between dapoxetine and CYP isoform inducers or inducers are unlikely. In vitro studies have shown that tadalafil does not inhibit or induce CYP isoforms 13 and is therefore not expected to have clinically significant pharmacokinetic interactions with dapoxetine. Sildenafil does not induce CYP isoforms in vitro but may partially inhibit some CYP isoforms, 14 however, it is unlikely that maximum plasma concentrations (1 μM) associated with a maximum dose of 100 mg affect the pharmacokinetics or metabolism of dapoxetine.

Although the known metabolic pathways and results of inhibition and induction in vitro for ever long tablet in karachi, sildenafil and tadalafil indicate that co-administration would result in few pharmacokinetic effects, this definitive clinical trial was performed for several reasons. First, in vitro data does not always reliably predict pharmacokinetic interactions in vivo, 15 and an appropriately designed clinical trial is needed in order to definitively assess the potential for in vivo interaction between medicinal products. Second, in vitro data provide no information on the safety and tolerability of concomitant medications. Even in the absence of pharmacokinetic interaction between drugs and drugs, it is possible that safety and tolerability can be altered when two drugs are administered. Finally, as many men suffer from both PE and ED and are likely to be treated concomitantly for both conditions, PDE-5 inhibitors are the most likely concomitant therapy to be taken with dapoxetine. The potential for interactions must therefore be evaluated in a clinical study.

As a result, this study investigates the effects of PDE-5 inhibitors on tatalin and sildenafil in pharmacokinetics and everlong dapoxetine tolerability of healthy voluntary men. Sildenafil and tadalafil are selected as PDE-5 inhibitors, because they are often prescribed and different from their parmacokinetic properties. Sildenafil has a small half life of about 4 h, 14 while tadalafil has a higher than half life of 17.5h.

Methods and Materials

Healthy men (aged 18-45 years old, N = 24) within 20% of the normal weight for height and shape and with blood pressure (BP) within range 90- 140 mmHg systolic and 50-90 mmHg diastolic. Examples of medical history, physical examination, blood chemistry, complete blood count (CBC), urinalysis, and electrocardiogram (ECG) clinic, or if there is a positive screen in the clinic urine drug or alcohol breath test. All subjects are required to use the medically accepted method of contraception throughout the study period and within 3 months of completing the study. Alcohol, caffeine, and grapefruit consumption are not allowed within 48 hours before each dose, and caffeine is limited to 450 mg / day; smoking or tobacco use within the last 3 months is unavailable. Examples are not included when they use any prescription or over-the-counter medications (except acetaminophen or vitamins) within 7 days before each dose, to minimize the effect of the cause to study.