Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.

Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.estrogen receptor ͉ methylation ͉ transcription ͉ histone

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.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABAA) a2,3 receptor modulator intended for the treatment of anxiety. • The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied. WHAT THIS STUDY ADDS • The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer. • The follow-up clinical studies in healthy volunteers demonstrated that the expected efficacious daily dose of AZD7325 only weakly induced the pharmacokinetics of the CYP3A4 sensitive substrate, midazolam, and had no effect on the pharmacokinetics of the CYP1A2 substrate, caffeine. There was no apparent change in AZD7325 exposure following co-administration of midazolam or caffeine compared with AZD7325 alone. • The study demonstrated that clinical exposure of the inducer plays a critical role in the determination of cytochrome P450 induction risk of a drug candidate. AIM(S) To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities. METHODS Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects. RESULTS The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 mM of AZD7325, in the range of 17.9%-54.9% and 76.9%-85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma Cmax of 0.2 mM after 10 mg daily dosing to steady-state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81-fold, 90% CI 0.77, 0.87), but had no effect on midazolam Cmax (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h-1 (midazolam alone) to 76 l h-1 when co-administered with AZD7325. The AUC and Cmax of caffeine were not changed after co-administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively. CONCLUSIONS While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.

Dapoxetine is being investigated for the treatment of premature ejaculation. This study evaluated the potential pharmacokinetic and cognitive interactions of dapoxetine 60 mg with ethanol 0.5 g/kg in a single-center, double-blind, randomized, placebo-controlled crossover study in healthy adult male participants (n = 24). Dapoxetine was rapidly absorbed and eliminated; peak concentrations were noted 1.47 hours after administration and decreased with an alpha half-life of 1.33 hours and a terminal half-life of 15.6 hours. Pharmacokinetic parameters (C(max), AUC(infinity), t((1/2)), and t(max)) of dapoxetine were not altered with concurrent ethanol consumption. Furthermore, coadministration of dapoxetine did not affect the pharmacokinetics of ethanol or potentiate the cognitive and subjective effects of ethanol.