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DRUG INTERACTIONS |
From ALZA Corporation, Mountain View, California (Dr Modi, Dr Dresser, Dr Desai) and Cognitive Drug Research Ltd, CDR House, Goring-on-Thames, UK (Mr Edgar, Dr Wesnes).
Address for reprints: Address for correspondence: Nishit B. Modi, PhD, ALZA Corporation, 1900 Charleston Road, Building M11-4A, Mountain View, CA 94043; e-mail: nmodi{at}alzus.jnj.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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, t
, and tmax) 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.
Key Words: dapoxetine • ethanol • pharmacokinetics • cognition
Dapoxetine is a short-acting SSRI developed as an on-demand treatment for PE that is rapidly absorbed following oral administration, with peak plasma concentrations approximately 1 hour after administration.8 Dapoxetine elimination is rapid and biphasic; its alpha half-life is approximately 1.4 hours, and its terminal half-life is approximately 20 hours.8 Dapoxetine-N-oxide, the primary circulating phase I metabolite, has weak serotonin receptor binding and transport inhibition in vitro (>250-fold less than dapoxetine) and does not contribute to clinical efficacy. Desmethyldapoxetine has a similar pharmacologic potency to dapoxetine in vitro but accounts for <3% of circulating dapoxetine species.
More than 70% of men in the United States consumed alcohol in 2002.9 Ethanol has known pharmacodynamic effects on cognitive function, such as impaired reaction time and recall. Peak plasma ethanol concentrations are observed approximately 2 hours after oral administration, and a dose of 0.7 g/kg is associated with a maximum serum ethanol concentration of 502 µg/mL.10 This study was designed to examine the potential pharmacokinetic, cognitive, and subjective interactions between dapoxetine and ethanol in healthy volunteers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was a single-center, double-blind, randomized, 4-treatment, 4-period, crossover study in healthy adult males, approved by the Ethics Committee of the participating study center (Charterhouse Clinical Research Unit, Ravenscourt Park Hospital, Ravenscourt Park, London, UK) and conducted in accordance with good clinical practice and the International Conference on Harmonization guidelines and Ethics Committee policies, including the ethical principles that have their origin in the Declaration of Helsinki on biomedical research involving human participants. Before participation, each participant was required to read, sign, and date an Ethics Committee-approved consent form explaining the nature, purpose, and possible risks and benefits of the study, as well as the duration of participation.
Participants were assigned randomly to 1 of 4 treatment sequences and received each of the following 4 treatments: (1) a placebo tablet followed by ethanol 0.5 g/kg in ginger ale ("ethanol"), (2) dapoxetine 60 mg (Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ) followed by ethanol 0.5 g/kg in ginger ale ("dapoxetine + ethanol"), (3) dapoxetine 60 mg followed by ginger ale as placebo for ethanol ("dapoxetine"), and (4) a placebo tablet followed by ginger ale ("placebo"). Ethanol or ginger ale was administered 30 minutes after dapoxetine or placebo to provide peak concentrations of each at approximately the same time. For the placebo drinks, ethanol-soaked gauze was placed in a double-walled container used to carry the drinks, which were covered in plastic wrap; doses of ethanol in ginger ale were prepared in similar containers covered in plastic wrap. Participants drank doses of either ethanol or placebo through a straw that protruded through the plastic wrap. A washout period of 5 to 21 days was required between treatments.
Assessments
At the initial screening visit, a medical history was obtained, and a physical examination was performed, including vital signs (heart rate, BP, and respiratory rate), 12-lead ECG, blood chemistry, complete blood count, and urinalysis. At each visit, participants were required to pass a urine drug screen and an alcohol breath test. Vital signs were measured at 0 (predose), 1, 2, 4, 6, 8, and 24 hours after administration of dapoxetine or placebo dapoxetine. At study termination, the physical examination, laboratory assessments, vital signs, and an ECG were repeated. All adverse events (AEs) were recorded and assessed in terms of severity and relationship to study drug and followed until resolution or until the end of the study.
Plasma Analysis for Dapoxetine and Its Metabolites
Blood samples (5 mL) were collected at 0, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after administration of dapoxetine for the measurement of dapoxetine and its metabolites, desmethyldapoxetine and dapoxetine-N-oxide, using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, with a minimum quantifiable dapoxetine concentration of 1.00 ng/mL and minimum quantifiable desmethyldapoxetine and dapoxetine-N-oxide concentrations of 0.200 ng/mL, using dapoxetine-d7, desmethyldapoxetine-d7, and dapoxetine-N-oxide-d7 as internal standards. Positive ions were monitored by MS/MS in the multiple-reaction monitoring mode for dapoxetine (m/z transition from 306.5 to 157.2), dapoxetine-d7 (m/z transition from 313.5 to 164.2), desmethyldapoxetine (m/z transition from 292.3 to 157.2), desmethyldapoxetine-d7 (m/z transition from 299.3 to 164.2), dapoxetine-N-oxide (m/z transition from 322.3 to 157.2), and dapoxetine-N-oxide-d7 (m/z transition from 329.3 to 164.2). The calibration curve was linear from 1.00 to 1000 ng/mL for dapoxetine and from 0.200 to 200 ng/mL for the metabolites. This method has been described previously.11
Precision and accuracy were determined by replicate analyses of human plasma quality-control samples spiked with dapoxetine and the metabolites. Precision was measured as the percent coefficient of variation of the quality control samples. The ranges of interassay precision were as follows: for dapoxetine, 6.01% to 16.1%; for desmethyldapoxetine, 4.61% to 16.0%; and for dapoxetine-N-oxide, 3.93% to 18.2%. Accuracy was expressed as the percent difference between the mean value for each pool and the theoretical concentration (% bias). The ranges of interassay accuracy were as follows: for dapoxetine, -2.49% to 3.78%; for desmethyldapoxetine, -8.86% to 9.85%; and for dapoxetine-N-oxide, -1.25% to 3.47%.
Plasma Analysis for Ethanol
Additional blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after administration of dapoxetine for ethanol analysis using a validated high-resolution gas chromatography with mass spectrometry (GC/MS) method, with a minimum quantifiable ethanol concentration of 2.74 µg/mL and a calibration curve that was linear from 2.74 to 992.0 µg/mL. Precision and accuracy were calculated as described above; the range of interassay precision for ethanol was 2.4% to 5.1%, and the range of interassay accuracy was -4.0% to 0.9%.
Analysis of Pharmacokinetic Parameters
Maximum plasma concentration (Cmax), time to Cmax (tmax), apparent half-life (t), alpha and terminal t, and area under the plasma concentration versus time curve (AUC) were estimated for ethanol, dapoxetine, desmethyldapoxetine, and dapoxetine-N-oxide. For dapoxetine and its metabolites, a 2-compartment model with first-order absorption and elimination was used (WinNonMix software, Version 2.0.1, Pharsight Corporation, Mountain View, Calif).12
Cognitive and Subjective Assessments
Cognitive function was measured using a battery of tasks from the Cognitive Drug Research (CDR) computerized cognitive assessment system.13,14 Prior to the first study day, cognitive function was measured 4 times, twice on each of 2 days, with 
1 hour between tests, to familiarize participants with the tests and to minimize any learning effects during the study. The CDR tests were conducted before dosing and 0.5, 1.5, 2.5, 4, 6, 8, 12, and 24 hours after administration of study drug. The following tests were performed: Immediate Word Recall (IWR), Simple Reaction Time (SRT), Digit Vigilance Task (DV), Choice Reaction Time (CRT), Visual Tracking Task (Tracking), Spatial Working Memory (SWM), Numeric Working Memory (NWM), Delayed Word Recall (DWR), Word Recognition (WR), Digit Symbol Substitution Test (DSST), and the Bond and Lader Visual Analog Scale (VAS) of Mood and Alertness,15 a questionnaire of 16 analog scales that derives 3 factors that assess change in self-rated alertness, self-rated calmness, and self-rated contentment. Two composite scores from the CDR tests were derived: (1) power of attention, which combines the reaction time measures from the 3 attention tests (ie, SRT, CRT, and DV), and (2) continuity of attention, which combines the accuracy measures from the 3 attention tests (ie, SRT, CRT, and DV).14
Statistical Analysis
Statistical analyses were conducted using SAS (SAS Institute, Inc, Cary, NC). Pharmacokinetic parameters for dapoxetine and ethanol were compared between the dapoxetine alone and dapoxetine + ethanol treatments using a mixed-effect analysis of variance (ANOVA) that included treatment, period, and sequence as fixed effects and subject within sequence as a random effect.16,17 Log-transformed dapoxetine AUC and Cmax values for dapoxetine and dapoxetine + ethanol were compared using the least squares estimate of the mean parameters for the ratio of dapoxetine + ethanol to dapoxetine alone; ethanol alone was compared to dapoxetine + ethanol in the same manner.
For cognitive and subjective assessments, a repeated-measures ANOVA was used that included fixed effects of sequence, treatment, period, time, and treatment-by-time interaction, as well as a random effect of subject within sequence. For each CDR measure, pre-dose (baseline) data for each period were subtracted from those at each postdosing time point to derive the difference from baseline scores, on which the analyses were performed. If the treatment-by-time interaction was significant (
<0.01), a standard ANOVA model for crossover designs, which included fixed effects of sequence, treatment, and period, as well as the random effect of subject within sequence, was used to compare the pharmacodynamic measure at each time point.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Analysis
Dapoxetine
The pharmacokinetics of dapoxetine were not affected by coadministration of ethanol 0.5 mg/kg (Figure 1). Dapoxetine was rapidly absorbed, with maximal plasma concentrations 1.47 ± 0.51 hours after administration (Table I). Elimination was rapid and biphasic; the alpha and terminal half-life was 1.33 ± 0.14 and 15.6 ± 0.81 hours, respectively. By 24 hours after administration, plasma dapoxetine concentrations had decreased to 4.5% of Cmax. The pharmacokinetic parameter values for dapoxetine were not affected by ethanol coadministration, as noted by the similar peak concentrations and AUC values. The 90% confidence intervals (CIs) for the ratio of (dapoxetine + ethanol)/(dapoxetine) for lnCmax and for lnAUC were within 80% to 125%, indicating that ethanol did not affect the pharmacokinetics of dapoxetine.
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Desmethyldapoxetine and Dapoxetine-N-Oxide
Ethanol did not affect the pharmacokinetics of desmethyldapoxetine or dapoxetine-N-oxide (Table I). For desmethyldapoxetine, the 90% CIs of the (dapoxetine + ethanol)/(dapoxetine) ratio for lnCmax were within 80% to 125%, whereas the 90% CI for the lnAUC ratio was slightly outside the 80% to 125% range, but the 2 treatments were not significantly different by ANOVA (P = .258, dapoxetine vs dapoxetine + ethanol). For dapoxetine-N-oxide, the 90% CIs of the (dapoxetine + ethanol)/(dapoxetine) ratios for lnCmax and for lnAUC were also within the 80% to 125% no-effect boundary.
Coadministration of ethanol did not affect the metabolism of dapoxetine to desmethyldapoxetine or dapoxetine-N-oxide; the AUC ratio for (dapoxetine)/(desmethyldapoxetine) was similar for dapoxetine and dapoxetine + ethanol (5.91 ± 1.4 and 6.57 ± 2.2, respectively), as was the AUC ratio for (dapoxetine)/(dapoxetine-N-oxide) (1.23 ± 0.24 and 1.27 ± 0.24, respectively).
Ethanol
Ethanol pharmacokinetics were not affected by coadministration of dapoxetine (Table II); plasma ethanol concentrations over time are shown in Figure 2. The 90% CIs of the (dapoxetine + ethanol)/(ethanol) ratio for lnCmax and for lnAUC were within 80% to 125%.
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Cognitive and Subjective Assessments
The analysis focused on the approximate time of peak plasma concentrations of both ethanol and dapoxetine (1.5 hours). Area under the effect curve analyses were conducted, and no significant differences between treatments were observed; however, there was a high degree of variability across time points. Peak concentrations of dapoxetine occurred approximately 1.5 hours after administration, whereas peak concentrations of ethanol occurred approximately 1 hour after administration (ethanol was administered 30 minutes after dapoxetine, to match the time to peak concentration for both agents). Ethanol 0.5 g/kg impaired measures of attention and verbal recall and recognition; effects peaked at 1.5 hours and resolved by 4 hours, consistent with the plasma profile of ethanol (Figure 2). Coadministration of dapoxetine did not potentiate the cognitive and subjective effects of ethanol (Figure 3, Table III).
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At 1.5 hours, simple reaction time, self-rated contentment, and power of attention and continuity of attention were significantly affected relative to placebo following administration of ethanol alone (P < .05, Figure 3A). A trend toward significance was noted for digit vigilance and delayed word recall following treatment with ethanol alone (P < .1). Fewer words were recalled correctly during the Delayed Word Recall test, and subjects reported lower levels of contentment and alertness following dapoxetine compared with placebo (P < .05). With dapoxetine + ethanol, simple reaction time, response time in digit vigilance, and power of attention all increased significantly (P < .05) compared to both placebo and dapoxetine alone but not compared to ethanol alone.
At 1.5 hours after administration, dapoxetine alone significantly decreased the percentage of correctly recalled words on the DWR, whereas ethanol alone significantly decreased the score for continuity of attention (P < .05 vs placebo for both; Table III). With dapoxetine + ethanol, the percentage of words correctly recalled on both the IWR and DWR was decreased, as was the score for continuity of attention (P < .05 vs placebo for all).
Following dapoxetine administration, Bond and Lader scores decreased for alertness (P < .05 vs placebo) and contentment (P < .05 vs placebo and ethanol alone; Figure 3B); following ethanol administration, Bond and Lader scores for contentment were increased (P < .05 vs placebo and dapoxetine alone). Following dapoxetine + ethanol, Bond and Lader scores were decreased for alertness (P < .05 vs placebo and ethanol alone) and contentment (P < .05 vs ethanol alone).
Adverse Events
Most AEs were of mild or moderate severity. No serious AEs were reported. A total of 28.6% of participants (6/21) reported AEs with ethanol, 75.0% (15/20) reported AEs with dapoxetine + ethanol, 52.2% (12/23) reported AEs with dapoxetine, and 38.1% (8/21) reported AEs with placebo. Somnolence was the most common AE (9.5% with ethanol, 30.0% with dapoxetine + ethanol, 13.0% with dapoxetine, and 9.5% with placebo). One participant experienced somnolence rated as severe during the dapoxetine treatment period. Other AEs reported by at least 2 participants on any treatment included headache, nausea, abnormal thinking, alcohol intolerance, asthenia, chills, euphoria, neurosis, and blurred vision. No clinically important changes in laboratory values, vital signs, or ECGs were seen.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Although SSRI antidepressants are sometimes used in the treatment of PE,4,6,7 they are not indicated for this application and may require days to weeks to reach the maximum concentrations necessary for effective treatment of depression and/or PE.5 The pharmacokinetics of SSRI antidepressants are generally not affected by consumption of moderate amounts of alcohol; fluvoxamine,18 fluoxetine,19 and venlafaxine20 have not shown pharmacokinetic alterations with concurrent alcohol consumption. For example, fluvoxamine 50 mg had no clinically significant effect on the pharmacokinetics of intravenous or oral alcohol (40 mg); however, the mean AUC(0-8) of alcohol increased significantly following multiple doses of fluvoxamine in comparison with placebo.18 Results from another study demonstrated that coadministration of fluoxetine (30 and 60 mg) with ethanol (45 mL absolute alcohol) did not alter the plasma or blood concentrations of fluoxetine or alcohol compared with either drug alone.19 In a separate study, administration of alcohol following multiple doses of fluoxetine or amitryptaline (a tricyclic antidepressant) resulted in decreased average alcohol concentrations compared with placebo.21
Several cognitive measures were impaired following ethanol 0.5 g/kg in this study, which was broadly consistent with previously characterized effects of ethanol22; this dose (
3 drinks) has been used in other drug interaction studies,20 and dapoxetine 60 mg was the highest dose studied in phase III trials.23 Peak plasma ethanol concentrations observed here (428-440 µg/mL) were comparable to previously reported maxima of 502 µg/mL and 640 µg/mL following doses of 0.7 g/kg10 and 40 mg,18 respectively. Dapoxetine administered alone was associated with declines in delayed word recall, self-rated alertness, and self-rated contentment. Although ethanol + dapoxetine yielded significant impairment on several tests compared with placebo, none were significantly different from those observed with ethanol alone. These results suggest that the addition of dapoxetine did not result in impairment beyond that associated with ethanol.
SSRI antidepressants have not generally been shown to potentiate the cognitive effects of alcohol. Alcohol impaired measures of cognitive function, whereas 50 mg fluvoxamine did not potentiate the effects of alcohol, although 2 measures of cognitive function (speed of responding in the vigilance task and word recognition sensitivity) were possibly affected by fluvoxamine.18 In another study, fluvoxamine tended to improve recognition but not free recall of words.24 Similarly, single and multiple doses of fluoxetine did not affect psychomotor activity (stability of stance, motor performance, or manual coordination) or subjective effects of alcohol.19 In another study, fluoxetine had no effect on auditory reaction time, DSST, or body sway with eyes open or closed but did result in a decrease from baseline in immediate and delayed word recall.21 Coadministration of fluoxetine with alcohol significantly slowed auditory reaction time, reduced DSST, and increased body sway in both the eyes open and closed conditions and produced further decreases in immediate and delayed word recall.21
Most AEs noted in this study were mild or moderate in severity. The overall rate of AEs was high, and 38% of participants reported AEs with placebo. Although this study was not designed to compare the rate of AEs between treatments, coadministration of dapoxetine with ethanol appeared to have an additive rather than a synergistic effect on the total number of AEs reported, suggesting that ethanol and dapoxetine induce AEs (such as dizziness, nausea, and diarrhea) through different mechanisms.
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CONCLUSIONS |
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ACKNOWLEDGEMENTS |
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REFERENCES |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
