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PHARMACOKINETICS |
From ALZA Corporation, Mountain View, California.
Address for reprints: Nishit B. Modi, ALZA Corporation, 1900 Charleston Road, Building M11-4A, Mountain View, CA 94043.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Dapoxetine • pharmacokinetics • premature ejaculation
SSRIs were intended for chronic use in the treatment of depression and so were designed to have pharmacokinetic profiles that would allow them to attain constant systemic concentrations with long-term administration—they may require days to weeks to reach maximum steady-state concentrations, and they exhibit significant accumulation with daily dosing.7 As is the case with depression, SSRIs are also most commonly given on a chronic daily dosing schedule for the treatment of PE.4,6,8-12 In addition to the potentially desirable side effect of delayed ejaculation, this dosing regimen for long-acting SSRIs is associated with undesirable sexual side effects, such as decreased libido and erectile dysfunction.4,6,8-12
Ideally, a pharmacologic agent intended to delay ejaculation for the treatment of PE should be effective with on-demand dosing to avoid adverse effects associated with chronic administration and would achieve a pharmacologic effect on the first dose. Such an on-demand compound would, in general, require a pharmacokinetic profile with 3 attributes: rapid absorption to allow a fast pharmacodynamic effect, adequate bioavailability to establish therapeutic exposure at the target site, and rapid elimination to reduce total drug exposure and minimize the incidence of side effects. Dapoxetine (Figure 1) is a serotonin transporter inhibitor that is being developed specifically as an on-demand oral treatment of PE. Dapoxetine is extensively metabolized by multiple enzymes (eg, cytochrome P450 isoforms and FMO1) and is excreted in the urine primarily as metabolized drug (unpublished results). The primary metabolite in the circulation is dapoxetine-N-oxide, which has shown weak in vitro receptor binding and transport inhibition (>250-fold less than dapoxetine) and does not contribute to clinical efficacy. Other phase 1 metabolites of dapoxetine that may be present in plasma include desmethyldapoxetine and didesmethyldapoxetine, which have similar pharmacologic potency to dapoxetine in vitro but account for less than 3% of the circulating dapoxetine species. This study was designed to assess the dose proportionality and pharmacokinetics of dapoxetine following administration of single and multiple doses of 30 and 60 mg to healthy volunteers.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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450 mg per day; smoking or tobacco use within the previous 3 months was not permitted. Subjects were excluded if they had used any prescription or over-the-counter medications (excluding acetaminophen and multivitamins) within 7 days before study start and throughout the study period, unless given prior approval.
Study Design
This was a single-center, randomized, single- and multiple-dose, open-label, 2-treatment, 2-period, crossover study. The protocol was approved by the Institutional Review Board (IRB) of the participating study center (MDS Pharma Services, Neptune, NJ), and the study was conducted in accordance with the United States Code of Federal Regulations (CFR), International Conference of Harmonisation (ICH) Guidelines, and IRB policies, including the ethical principles that have their origin in the Declaration of Helsinki on biomedical research involving human subjects. Before study participation, each subject was required to read, sign, and date an IRB-approved consent form explaining the nature, purpose, and possible risks and benefits of the study and the duration of an individual's participation.
Dapoxetine HCl tablets (30- and 60-mg equivalent of dapoxetine) were manufactured by Johnson & Johnson Pharmaceutical Research and Development (Beerse, Belgium). Subjects were randomly assigned to 1 of 2 dapoxetine treatment sequences and received each of the following 2 treatments: (1) a single oral dose of dapoxetine 30 mg on day 1 (single-dose phase) and on days 4 to 9 (multiple-dose phase) and (2) a single oral dose of dapoxetine 60 mg on day 1 (single-dose phase) and on days 4 to 9 (multiple-dose phase). Each treatment period was followed by a washout period of 7 to 17 days, starting from the time of the last dose.
Assessments
At the initial screening, a physical examination, urine drug screen, standard laboratory tests (fasting blood chemistry, complete blood count, urinalysis), and a 12-lead ECG were performed. A medical history was also taken. At the beginning of each treatment period (day 0), an alcohol test and a urine drug screen were performed, and a blood sample was obtained for hemoglobin measurements. Vital signs (heart rate, blood pressure, and respiratory rate) were measured following administration of study drug on day 1, after the subject had been resting supine for 5 minutes and again after the subject had been standing erect for 5 minutes, at 1 hour and 0.25 hours before administration of dapoxetine (ie, -1 and -0.25), and 1.5, 4, 6, 8, 24, 48, and 72 hours after dosing on days 1 and 9 and predose and 1.5 hours after dosing on days 4 to 8. At study termination, a medical history was obtained, and standard laboratory tests, a 12-lead ECG, and vital sign assessments were performed. Dapoxetine was administered on days 1, 4, 5, 6, 7, 8, and 9 in each treatment period, with no doses administered on days 2 and 3. On days 1 and 9 of each treatment period, subjects fasted for at least 10 hours before dosing and for 4 hours after dosing.
All adverse events (AEs) were recorded and assessed for severity (mild, moderate, severe) and relationship to study drug. Serious, life-threatening, and unexpected AEs were defined in accordance with 21 CFR Part 312.32 and were consistent with the ICH guidance document E2A "Clinical Safety Data Management: Definitions and Standards for Expedited Reporting." Ongoing AEs were followed until they resolved or the patient became medically stable.
Pharmacokinetics
Blood samples (7 mL) were collected from each subject to determine plasma concentrations of dapoxetine and its 2 primary phase 1 metabolites (desmethyldapoxetine and dapoxetine-N-oxide) at 0 (predose), 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after the single-dose phase (day 1) and after the last dose of the multiple-dose phase (day 9) in each period. Predose blood samples were also obtained on days 7 and 8.
Drug assay. Plasma samples were analyzed for the enantiomers of dapoxetine, desmethyldapoxetine, and dapoxetine-N-oxide using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. The R- and S-isomers of dapoxetine and its metabolites, dapoxetine-N-oxide and desmethyldapoxetine, were measured to monitor for potential in vivo stereoconversion. Internal standards (R- and S-dapoxetine-d7, R- and S-desmethyldapoxetine-d7, and R- and S-dapoxetine-N-oxide-d7) were added to the plasma samples, and the analytes and internal standards were extracted from plasma by a 96-well solid phase extraction (SPE) using a Waters Oasis MCX 96-well SPE plate. Sample extraction steps were controlled and automated using a TOMTEC Quadra 96 Model 320. Plasma extracts were evaporated to dryness and reconstituted in an appropriate solvent before injection onto the LC/MS/MS, using a Chromtec Chiral AGP column. The assay was validated on a SCIEX instrument platform equipped with a turbo ion spray interface, and positive ions were monitored in the selected reaction monitoring mode. Mass transitions (m/z) were detected as follows: S- and R-dapoxetine, 306.2 to 261.2; S- and R-desmethyldapoxetine, 292.2 to 261.1; and S- and R-dapoxetine-N-oxide, 322.2 to 261.2. The lower limit of quantification was 1.00 ng/mL for R- and S-dapoxetine, 0.20 ng/mL for R- and S-desmethyldapoxetine, and 0.50 ng/mL for R- and S-dapoxetine-N-oxide.
Precision was measured as the percentage coefficient of variation of the values for replicate measurements of samples used for calibration. The mean interassay precision ranged from 6.0% to 19.5% for S-dapoxetine and from 4.6% to 5.7% for R-dapoxetine. For S- and R-desmethyldapoxetine, the mean interassay precision ranged from 5.7% to 8.5% and from 6.1% to 9.0%, respectively. For S- and R-dapoxetine-N-oxide, the mean interassay precision ranged from 5.6% to 6.8% and from 4.3% to 6.2%, respectively.
Accuracy was expressed as the percentage difference between the determined mean value for calibration solutions and their theoretical concentration. The mean interassay accuracy for S- and R-dapoxetine ranged from -2.6% to 5.2% and from -7.3% to 4.9%, respectively. For S- and R-desmethyldapoxetine, the mean interassay accuracy ranged from -7.6% to -3.0% and from -6.3% to -3.6%, respectively. For S- and R- dapoxetine-N-oxide, the mean interassay accuracy ranged from -3.2% to 1.1% and from -2.1% to -1.7%, respectively.
Pharmacokinetic analyses. Pharmacokinetic parameters for dapoxetine and its metabolites were estimated using noncompartmental pharmacokinetic methods. The maximum plasma concentration (Cmax), time to peak concentration (Tmax) on day 1 and day 9, trough concentration (Cmin) on day 9, and the time taken to decrease by one half of Cmax following Tmax (t50%Cmax) were observed values. The apparent elimination half-life (t1/2) on day 1 and day 9 was calculated as -(ln2)/ß, where ß is the slope of log-linear regression of the terminal phase of the concentration versus time curve. The area under the plasma concentration versus time profile from hour 0 to the last quantifiable concentration at time t (AUCt) on day 1 and day 9 was determined by the linear trapezoidal method, as was the AUC value for the first 24 hours (AUC0-24) on day 1 and day 9. The AUC value extrapolated to infinity (AUC
) on day 1 was calculated as AUC =AUCt +Ct/k. Accumulation (R) was calculated as the ratio of AUC0-24 on day 9 to AUC0-24 on day 1. The average plasma concentration at steady state (Css) was calculated as AUC0-24/24 on day 9.
In addition, initial and terminal half-life values were estimated for dapoxetine using a 2-compartment model with first-order absorption and elimination (WinNonMix software, version 2.0.1, Pharsight Corporation, Mountain View, Calif).
Dose proportionality was assessed using the dapoxetine 60 mg:dapoxetine 30 mg ratio of dose-normalized log-transformed Cmax and AUC on day 1 and on day 9. Single- and multiple-dose pharmacokinetics was compared using the day 9:day 1 ratio of Cmax and of AUC for the 30- and 60-mg doses of dapoxetine.
Statistical Analysis
A mixed-effect analysis of variance (ANOVA) model, which included treatment, period, and sequence as fixed effects and subject within sequence as a random effect, was used for the analysis of dapoxetine pharmacokinetic parameters (ie, log-transformed AUC and Cmax).13 The least-squares estimate of the mean for the ratio and a 90% confidence interval (CI) are presented.14 The pharmacokinetics of dapoxetine was considered dose proportional if the 90% CI for the dapoxetine 60 mg:dapoxetine 30 mg ratio of lnCmax and of lnAUC fell within 80% to 125% (following dose normalization). The pharmacokinetics of dapoxetine was considered time invariant if the 90% CI for the ratio of AUC0-24 on day 9 to AUC on day 1 included 100%. Data from subjects who had emesis at or before 2 times the median Tmax of dapoxetine were excluded from the statistical analysis.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Dapoxetine, Desmethyldapoxetine, and Dapoxetine-N-oxide
The pharmacokinetics of dapoxetine, desmethyldapoxetine, and dapoxetine-N-oxide following single and multiple doses of dapoxetine 30 and 60 mg are summarized in Table I, and dapoxetine plasma concentration versus time profiles are illustrated in Figure 2 and Figure 3. Dapoxetine tablets contain only the S-isomer of dapoxetine, and no in vivo stereoconversion of S-dapoxetine to R-dapoxetine or of the S-isomer metabolites to the R-isomers was noted; therefore, the R-analytes are not discussed further, and all references to dapoxetine, desmethyldapoxetine, and dapoxetine-N-oxide denote the S-isomer. Briefly, dapoxetine was rapidly absorbed, with maximal plasma concentrations noted approximately 1 hour after single and multiple doses of dapoxetine 30 and 60 mg. Elimination of dapoxetine was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours, and plasma dapoxetine concentrations were approximately 5% of peak concentrations by 24 hours after dosing.
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Single-dose pharmacokinetics of dapoxetine. Single doses of dapoxetine 30 and 60 mg were rapidly absorbed, with maximum plasma concentrations of 297 and 498 ng/mL noted 1.01 and 1.27 hours after oral administration, respectively (Table I, Figure 2, Figure 3). Elimination of dapoxetine was rapid and biphasic for both the 30- and 60-mg doses, with an initial half-life of 1.31 and 1.42 hours, respectively, and a terminal half-life of 18.7 and 21.9 hours, respectively. By 24 hours after administration, plasma dapoxetine concentrations were 3.5% and 3.9% of peak values for 30 and 60 mg dapoxetine, respectively; the time for plasma dapoxetine concentrations to fall to 50% of peak concentrations was 1.92 and 2.14 hours, respectively.
Dose proportionality was confirmed by comparing the log-transformed Cmax and AUC values for the 30- and 60-mg doses; the dose-normalized dapoxetine 60 mg:dapoxetine 30 mg ratio was 86.7% (90% CI = 79.70%-94.23%) for lnCmax and 97.3% (90% CI = 91.43%-103.57%) for lnAUC. The 90% CIs were within the standard 80% to 125% no-effect boundary; thus, dapoxetine exhibited dose-proportional pharmacokinetics over the range of doses studied.
Multiple-dose pharmacokinetics of dapoxetine. The pharmacokinetics of dapoxetine was unaffected by multiple dosing, as demonstrated by similar values for the various pharmacokinetic parameters on day 1 and day 9 (Table I, Figure 2, Figure 3). Dapoxetine was rapidly absorbed after multiple doses of 30 and 60 mg, with peak plasma dapoxetine concentrations (349 and 596 ng/mL) noted 1.03 and 1.07 hours after oral administration on day 9, respectively; Cmax and Tmax were similar between the single- and multiple-dose regimens within each dapoxetine dose level. Elimination of dapoxetine after multiple doses of 30 and 60 mg was rapid; plasma dapoxetine concentrations for the 30- and 60-mg doses decreased to 5.5% and 6.6% of peak concentrations, respectively, by 24 hours following the last dose on day 9. The time taken for dapoxetine concentrations to decrease by 50% of Cmax was 1.83 and 2.28 hours after receiving multiple doses of dapoxetine 30 and 60 mg, respectively. Steady-state plasma concentrations were reached by the fourth dose of dapoxetine; the predose plasma concentrations of dapoxetine were comparable on days 7 to 9 for both the 30- and the 60-mg doses (P 
.59 and P .69, respectively, by ANOVA). Average steady-state concentrations were 64.7 and 122.9 ng/mL for dapoxetine 30 and 60 mg, respectively.
Accumulation was assessed by the ratio of AUC0-24 values between day 9 and day 1 (ie, the multiple-dose to single-dose ratio). On each of the multiple-dose treatment days, dapoxetine plasma concentrations decreased to approximately baseline values by the start of the next treatment day. Modest accumulation of dapoxetine (145% and 146%) was evident after multiple dosing with dapoxetine 30 and 60 mg, respectively.
Multiple dosing did not affect the dose proportionality of dapoxetine; the dose-normalized dapoxetine 60 mg:dapoxetine 30 mg ratio was 85.9% (90% CI = 80.19%-91.94%) for lnCmax and 96.2% (90% CI = 91.19%-101.45%) for lnAUC0-24. The 90% CIs were within the standard 80% to 125% no-effect boundary; thus, dapoxetine exhibited dose-proportional pharmacokinetics with multiple dosing.
Dapoxetine pharmacokinetics was time invariant; the 90% CIs for the ratio of AUC0-24 following multiple dosing to AUC following the single dose were 96.54% to 133.67% and 98.05% to 132.47% for dapoxetine 30 and 60 mg, respectively. The 90% CIs included 100%, indicating that dapoxetine pharmacokinetics was time invariant.
Single-dose pharmacokinetics of desmethyldapoxetine and dapoxetine-N-oxide. Following a single dose of dapoxetine, mean peak desmethyldapoxetine concentrations (9.48 and 17.7 ng/mL) were noted 2.74 and 2.78 hours after dosing with dapoxetine 30 and 60 mg, respectively (Table I). Mean terminal half-life values of desmethyldapoxetine after a single dose were 17.2 and 20.2 hours for the 30- and 60-mg doses, respectively. Dose proportionality of desmethyldapoxetine was confirmed by comparing the dose-normalized log-transformed Cmax and AUC values for the 30- and 60-mg doses; the dapoxetine 60 mg:dapoxetine 30 mg ratio was 97.0% (90% CI = 86.86%-108.33%) for lnCmax and 101.5% (90% CI = 89.06%-115.64%) for lnAUC. The 90% CIs are within the standard 80% to 125% no-effect boundary; thus, desmethyldapoxetine exhibits dose-proportional pharmacokinetics.
Mean peak dapoxetine-N-oxide concentrations (56.0 ng/mL and 111 ng/mL) were noted 2.13 and 2.35 hours after a single dose of dapoxetine 30 and 60 mg, respectively (Table I). The mean terminal half-life values for dapoxetine-N-oxide were 20.6 hours and 20.5 hours for the 30- and 60-mg doses, respectively. Dose proportionality was confirmed by comparing the dose-normalized log-transformed Cmax and AUC values for the 30- and 60-mg doses; the dapoxetine 60 mg:dapoxetine 30 mg ratio was 100% (90% CI = 96.23%-103.87%) for lnCmax and 102% (90% CI = 96.82%-107.37%) for lnAUC. The 90% CIs are within the standard 80% to 125% no-effect boundary; thus, dapoxetine-N-oxide exhibits dose-proportional pharmacokinetics.
The metabolic conversion of dapoxetine to desmethyldapoxetine and to dapoxetine-N-oxide was considered dose proportional; the ratios of dapoxetine: desmethyldapoxetine and dapoxetine:dapoxetine-N-oxide were comparable following single doses of dapoxetine 30 and 60 mg (Table II).
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Multiple-dose pharmacokinetics of desmethyldapoxetine and dapoxetine-N-oxide. The pharmacokinetics of desmethyldapoxetine and dapoxetine-N-oxide were also not affected by multiple dosing, as demonstrated by similar values for the various pharmacokinetic parameters on day 1 and day 9 (Table I). Desmethyldapoxetine rapidly reached peak concentrations (14.3 and 25.3 ng/mL), which were noted 2.53 and 2.63 hours following multiple doses of dapoxetine 30 and 60 mg. Dapoxetine-N-oxide peak concentrations (85.7 and 172 ng/mL) were noted 2.11 and 2.09 hours after multiple doses of dapoxetine 30 and 60 mg, respectively.
As with dapoxetine, accumulation was assessed by the ratio of AUC0-24 values between day 9 and day 1 (ie, the multiple-dose to single-dose ratio). Accumulation of desmethyldapoxetine (177% and 184%) and dapoxetine-N-oxide (178% and 177%) was evident after multiple dosing with dapoxetine 30 and 60 mg, respectively.
Multiple dosing did not affect the dose proportionality of desmethyldapoxetine or dapoxetine-N-oxide. For desmethyldapoxetine, the dose-normalized dapoxetine 60 mg:dapoxetine 30 mg ratio was 92.3% (90% CI = 86.00%-99.16%) for lnCmax and 99.0% (90% CI = 92.26%-106.22%) for lnAUC0-24. For dapoxetine-N-oxide, the dose-normalized dapoxetine 60 mg:dapoxetine 30 mg ratio was 101% (90% CI = 97.17%-105.36%) for lnCmax and 101% (90% CI = 95.40%-107.27%) for lnAUC0-24. The 90% CIs were within the standard 80% to 125% no-effect boundary; thus, desmethyldapoxetine and dapoxetine-N-oxide exhibited dose-proportional pharmacokinetics with multiple dosing of dapoxetine 30 and 60 mg.
Desmethyldapoxetine and dapoxetine-N-oxide also exhibited time-invariant pharmacokinetics. For desmethyldapoxetine, the 90% CI for the multiple dose:single dose AUC ratio was 93.78% to 152.45% for dapoxetine 30 mg and 94.29% to 148.76% for dapoxetine 60 mg. For dapoxetine-N-oxide, the 90% CI for the multiple dose:single dose AUC ratio was 89.42% to 123.73% for dapoxetine 30 mg and 91.05% to 121.57% for dapoxetine 60 mg. The 90% CIs contained 100%, indicating time-invariant pharmacokinetics.
The effect of multiple dosing on the metabolism of dapoxetine to desmethyldapoxetine or to dapoxetine-N-oxide was assessed through the mean ratios of AUC0-24 for dapoxetine:desmethyldapoxetine and dapoxetine: dapoxetine-N-oxide (Table II). The AUC ratios were comparable for single-dose versus multiple-dose dapoxetine at both the 30- and 60-mg doses, indicating that dapoxetine metabolism was not affected by multiple dosing.
Clinical Observations
Of the 42 subjects who received dapoxetine 30 and 60 mg, AEs were reported during the single-dose phase by 11 (26.2%) and 17 (40.5%) subjects, respectively, and during the multiple-dose phase by 19 (45.2%) and 17 (40.5%) subjects, respectively. Most AEs were mild or moderate in severity, and most were assessed as possibly or probably related to study drug. There were no serious AEs reported. The most commonly reported AEs were diarrhea, dizziness, and nausea (Table III). The incidences of nausea and dizziness across treatment phases (single and multiple doses) and across treatments (dapoxetine 30 and 60 mg) were similar. The incidence of diarrhea was higher in the 60-mg single-dose regimen than in the other treatment regimens. Diarrhea, dizziness, and nausea occurred more frequently on day 1 than on day 9, regardless of dose.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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While there are currently no pharmacologic agents indicated for the treatment of PE, SSRI antidepressants are sometimes prescribed because of their known side effect of delayed ejaculation.5,6 Two SSRIs, paroxetine and fluoxetine, have been studied in small trials to determine their benefit in the treatment of PE; their pharmacokinetic profiles are very different from that of dapoxetine.7,15,16 Fluoxetine absorption is slow compared to dapoxetine—maximal plasma concentrations of fluoxetine are reached 6 to 8 hours after oral administration.16 Fluoxetine has a long half-life of 1 to 4 days, and its active metabolite norfluoxetine has an even longer half-life of 7 to 15 days; accordingly, 2 to 4 weeks may be required to achieve steady state.16 The pharmacokinetics of fluoxetine is nonlinear, and multiple dosing results in disproportionate increases in Cmax and t1/2.16 Paroxetine is also slowly absorbed, requiring 5 hours to reach maximal concentrations.15 Elimination of paroxetine varies greatly with increased doses or multiple dosing; administration of paroxetine 20 mg for 15 days increases the half-life from 16.4 to 18.3 hours and from 9.8 to 21.0 hours with repeated once-daily dosing of paroxetine 30 mg.15 The AUC of paroxetine increases even more dramatically with multiple dosing, from 191 to 1481 ng•h/mL (at the 20-mg dose).15 Paroxetine also exhibits nonlinear pharmacokinetics and requires 7 to 14 days to reach steady state, while exhibiting approximately 8-fold accumulation.15
When used in the treatment of PE, long-acting SSRIs are usually prescribed with a chronic daily dosing schedule to ensure efficacy; recent work has explored on-demand use of such SSRIs for the treatment of PE.6,17 A recent study found that paroxetine retains its effectiveness if dosed daily for 2 weeks prior to being taken on demand17; the long half-life and high accumulation of paroxetine suggest that plasma concentrations of the drug may not return to baseline for an extended period. As such, on-demand dosing of paroxetine likely acts as a supplement to significant predose concentrations of drug, rather than as a single-dose treatment. In contrast, the rapid absorption and elimination exhibited by dapoxetine is more characteristic of a true on-demand formulation.
Most AEs noted with the 30- and 60-mg doses of dapoxetine, and for single and multiple doses of dapoxetine, were mild or moderate in severity; no serious AEs were reported. Safety assessments, including vital signs, ECGs, and clinical laboratory values, were not affected by single or multiple doses of dapoxetine at either dosing level. Of note, the total incidence of AEs during the multiple-dose phase included all events that occurred during the 5 days of continuous dosing and are generally comparable to the incidence of AEs following a single dose.
Dapoxetine undergoes rapid absorption and elimination, resulting in modest drug accumulation. The 30- and 60-mg doses of dapoxetine demonstrate dose-proportional pharmacokinetics, which is unaffected by multiple dosing. The pharmacokinetic characteristics of dapoxetine suggest that it merits further evaluation for the on-demand treatment of PE.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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