Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n ¼ 24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg þ tadalafil 20 mg, and dapoxetine 60 mg þ 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, whereas sildenafil increased the dapoxetine AUC inf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated.
Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.
Objective
To characterize the pharmacokinetics and safety of single and multiple doses of dapoxetine, a novel agent under development for the treatment of premature ejaculation, a urogenital disorder. Methods: This was a randomized, double‐blind, placebo‐controlled, single and multiple dose study in 77 healthy male volunteers. Dapoxetine was administered orally as a single dose of 60, 100, 140, or 160 mg or once‐daily for 6 days at 80, 100, or 120 mg. Pharmacokinetic parameters were determined by non‐compartmental methods. Safety was evaluated by physical exam; laboratory, vital signs and ECG measurements; and monitoring of adverse events. Results: Dapoxetine was quickly absorbed with peak plasma concentrations occurring at ~1.5 h after dosing followed by a rapid decline in plasma concentrations. Cmax and AUC increased proportionally up to 100 mg. Dapoxetine had a terminal half‐life of ~18 h. Single‐ and multiple‐dose pharmacokinetics were comparable. No serious adverse events were reported, and there were no clinically relevant changes in any clinical laboratory tests, vital signs, or ECG. Nausea, the most common adverse event, was mild or moderate. Conclusions: Following oral administration, dapoxetine was rapidly absorbed; a fast decline in plasma concentrations followed. Dapoxetine was well tolerated following single and multiple doses to healthy volunteers.
Clinical Pharmacology & Therapeutics (2004) 75, P32–P32; doi:
The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.
The pharmacokinetic results demonstrate that DDTDF is bioequivalent to the original fentanyl transdermal reservoir system after single and multiple applications.
This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capsules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUCinfinity ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.
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