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Pharmacokinetics of Dapoxetine, a New Treatment for Premature Ejaculation: Impact of Age and Effects of a High-Fat Meal

From ALZA Corporation, Mountain View, California (Dr Dresser, Dr Kang, Dr Staehr, Ms Gidwani, Ms Guo, Dr Modi), and the Department of Urology, Weill Medical College of Cornell University, New York–Presbyterian Hospital, New York, New York (Dr Mulhall).

Address for reprints: Mark J. Dresser, PhD, ALZA Corporation, 1900 Charleston Road, Building M11-4, Mountain View, CA 94043; e-mail: mdresser{at}alzus.jnj.com.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
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·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.

Key Words: Dapoxetine • pharmacokinetics • food • age • premature ejaculation

Dapoxetine is a serotonin transport inhibitor that has been developed specifically as an on-demand oral medication for the treatment of PE. Results of phase III clinical trials have shown that dapoxetine is effective in prolonging intravaginal ejaculatory latency time when administered 1 to 3 hours prior to sexual intercourse.⁵ Unlike SSRI antidepressants,⁶ dapoxetine has a pharmacokinetic profile characterized by peak plasma concentrations that occur approximately 1 hour after administration and an half-life of approximately 1.4 hours.⁷ By 24 hours, plasma dapoxetine concentrations are approximately 5% of peak values. Multiple enzymes, including cytochrome P450 isoforms and flavin-containing monooxygenase 1, are responsible for the metabolism of dapoxetine to its phase I metabolites, which include dapoxetine-N-oxide, desmethyldapoxetine, and didesmethyldapoxetine. Although dapoxetine-N-oxide is the primary metabolite in the circulation, in vitro studies have demonstrated that it has only weak receptor binding and transport inhibition (>250-fold less than dapoxetine) (unpublished observations). Desmethyldapoxetine and didesmethyldapoxetine have similar pharmacologic potency to dapoxetine in vitro but account for fewer than 3% of the circulating dapoxetine species.

The pharmacokinetics of some drugs may vary according to the age of the patient. For example, the pharmacokinetics of several SSRI antidepressants, such as citalopram⁸ and paroxetine,⁹ are altered in elderly men. Another common male sexual dysfunction, erectile dysfunction (ED), increases in prevalence with age; in contrast, the prevalence of PE remains relatively constant across age categories.^10,11 Because pharmacologic agents for the treatment of PE are therefore likely to be used by men of all ages, it is important to determine if the pharmacokinetic profile of dapoxetine is altered in older men.

Coadministration of food can also affect the pharmacokinetics of a number of drugs.¹² Although the SSRI antidepressants paroxetine, sertraline, and fluoxetine may be taken with or without food, their absorption and/or elimination may be affected by food consumption.^13-15

We present the results from 2 pharmacokinetic studies of dapoxetine that examined the effect of age (ie, young men vs elderly men), and the effect of food (ie, fasting vs a standardized high-fat meal) on dapoxetine pharmacokinetics.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Study Design and Subjects
Both studies were approved by the Institutional Review Board (IRB) of the respective study centers (West Pharmaceutical Services Inc, GFI Research Center, Evansville, Ind; Quintiles Phase I Services, Lenexa, Kan), and were conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. Before participation, subjects in each study were required to read, sign, and date an IRB-approved consent form explaining the nature, purpose, possible risks and benefits, and duration of the study.

Study 1: effect of age. A single-center, open-label, single-dose, single-period, parallel-group study was conducted to compare the pharmacokinetics of dapoxetine in young (18-45 years of age) and elderly (>65 years of age) men. Young and elderly men received a single dose of dapoxetine 60 mg. Dapoxetine hydrochloride tablets were manufactured by Johnson & Johnson Pharmaceutical Research & Development (Beerse, Belgium). Healthy male subjects within 20% of normal weight for height and build with supine blood pressure within the range of 90 to 160 mm Hg systolic and 50 to 100 mm Hg diastolic were enrolled.

Study 2: high-fat meal. A single-center, randomized, single-dose, open-label, 2-treatment, 2-sequence, 2-period, crossover study was conducted to evaluate the effect of a standardized high-fat meal on dapoxetine pharmacokinetics. Subjects were assigned to 1 of 2 treatment sequences and received both of the following treatments: a single dose of dapoxetine 60 mg taken after a high-fat breakfast (ie, fed) and a single dose of dapoxetine 60 mg taken in a fasted state (ie, fasted). The washout period between each treatment period was a minimum of 5 days and not more than 14 days. The composition of the meal was as described by the US Food and Drug Administration Guidelines.¹⁶ This study enrolled healthy male subjects, ages 18 to 45 years, within 20% of normal weight for height and build with supine blood pressure within the range of 90 to 140 mm Hg systolic and 50 to 90 mm Hg diastolic.

Exclusion criteria. Subjects were excluded from either study if they had clinically relevant abnormalities as determined by medical history, physical examination, blood chemistry, complete blood count (CBC), urinalysis, and electrocardiogram (ECG), or if they had a positive urine drug screen or alcohol breath test result. All subjects were required to use a medically acceptable method of contraception throughout the entire study period and for 3 months after study completion. Alcohol, caffeine, and grape-fruit consumption were not permitted within 48 hours prior to each dose, and caffeine was limited to 450 mg/d; smoking or tobacco use within the prior 3 months was not permitted. Subjects were excluded if they had used any prescription or over-the-counter medications (except for acetaminophen or vitamins) to minimize the effect of extraneous factors in the study. In addition, subjects in the effect-of-age study were permitted to use over-the-counter nonsteroidal anti-inflammatory drugs, aspirin, and lipid-lowering agents if they had been on a stable regimen of these agents for at least 2 months. In both studies, subjects were required to fast for 10 hours prior to and 4 hours after receiving study medications; subjects receiving the high-fat meal were required to fast for the same time period, with the exception of the meal provided at the study center.

Assessments
At the initial screening, the following were performed and/or assessed: a medical history, a physical examination, standard laboratory tests (including blood chemistry, CBC [hematocrit, hemoglobin, red blood cell count, white blood cell count with differential, and platelet count], and urinalysis), vital signs (heart rate, blood pressure, and respiratory rate), a urine drug screen, and an ECG. An alcohol breath test and a urine drug screen were performed prior to each treatment. Vital signs were measured before dosing (0 hours) and frequently for up to 72 hours after dosing. Blood samples for pharmacokinetic analyses were collected and analyzed as described below. At study termination, a physical examination was performed, along with standard laboratory tests and an ECG, and vital signs were recorded.

Adverse events were assessed by the investigator in terms of severity and relationship to study drug (probably related, possibly related, not related), and followed until resolution or until the event was medically stable.

Plasma Analysis
Blood samples (7 mL) for pharmacokinetic analyses were collected at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after administration of dapoxetine.

Both studies analyzed plasma for dapoxetine using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method (PPD Development, Richmond, Va). The assay was calibrated using dapoxetine-d₇ as an internal standard and was validated on a SCIEX instrument platform equipped with an electrospray ionization interface; the column used for chromatographic separation was a ThermoHypersil-Keystone Betasil C₈ column (2.1 mm x 50 mm, 5 µm). Positive ions were monitored by MS/MS in the multiple reaction monitoring mode for dapoxetine (mass-to-charge transition from 306.5 to 157.2) and dapoxetine-d₇ (mass-to-charge transition from 313.5 to 164.2).

This method was validated with a minimum quantifiable dapoxetine concentration of 1.00 ng/mL, and the calibration curve was linear in the range of 1.00 to 1000 ng/mL. Precision and the percentage of deviation from theoretical values were determined by replicate analyses of human plasma quality control samples spiked with dapoxetine. Precision was measured as the percentage coefficient of variation (%CV) of the values determined for each pool. For the effect-of-age study, the interassay precision for dapoxetine was 4.23% to 8.92%, and the interassay percentage of deviation from theoretical values for dapoxetine was –4.11% to 3.98%. For the effect-of-food study, the interassay precision for dapoxetine ranged from 4.60% to 11.2%, and the interassay percentage of deviation from theoretical values ranged from 0.460% to 3.85%.

Pharmacokinetic Analyses
Pharmacokinetic parameters (maximum plasma concentration, C_max; time to C_max, t_max; area under the plasma concentration versus time curve, AUC; and half-life, t) were estimated using standard methods.¹⁷ Descriptive pharmacokinetic parameters were calculated for dapoxetine using noncompartmental methods, and and terminal half-life values were determined using a 2-compartment model with firstorder absorption (WinNonMix software, version 2.0.1, Pharsight Corp, Mountain View, Calif).

Statistical Analyses
Pharmacokinetic parameters for dapoxetine were compared between young and elderly men using an analysis of variance (ANOVA), which considered group as a fixed effect. The group effect (elderly/young) was calculated based on log-transformed least square estimates of pharmacokinetic parameters (ie, lnC_max, lnAUC), as well as the associated 95% confidence intervals (CIs).¹⁸ The Wilcoxon rank-sum test was used to compare t_max values between treatment groups.

To assess the effect of food on dapoxetine pharmacokinetics, a mixed-effect 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 (AUC_inf and C_max).¹⁹ The fed:fasted ratio was determined for the log-transformed least square mean pharmacokinetic parameters (ie, lnC_max, lnAUC_inf), and the corresponding 90% CIs were computed.¹⁸

In both studies, data from any subject who vomited at or before 2 times the median t_max were excluded from the pharmacokinetic analyses.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Dapoxetine Pharmacokinetics in Young Men Versus Elderly Men
Subject disposition. In total, 36 subjects (18 young men and 18 elderly men) were enrolled and completed the study. The young men had a mean age of 28.9 years (range, 18-43 years), whereas the elderly men had a mean age of 70.2 years (range, 65-77 years). The mean weight for the young and elderly groups was 78.8 kg and 82.7 kg, respectively.

View larger version (10K): [in this window] [in a new window]   Figure 1. Plasma concentrations of dapoxetine in young and elderly men. Plasma concentrations of dapoxetine were measured after administration of dapoxetine 60 mg to young (age, 18-45 years) and elderly (age, >65 years) men.

Dapoxetine was rapidly absorbed in both young and elderly men. Mean peak concentrations of dapoxetine were similar between young and elderly men (338 and 310 ng/mL, respectively) and were noted at 1.29 and 1.28 hours after administration of dapoxetine, respectively. Dapoxetine was rapidly eliminated in both young and elderly men; plasma concentrations of dapoxetine decreased to 5% and 6% of peak concentrations by 24 hours after dosing in young and elderly men, respectively. The half-life of dapoxetine was similar in young and elderly men (1.46 and 1.49 hours, respectively). Mean AUC values were also similar in the 2 groups. The elderly:young ratios of the least square mean values of lnC_max and of lnAUC_inf for dapoxetine indicated that values for the 2 groups were not different (P = .497 and .400, respectively). Minimal accumulation of dapoxetine occurred in both young and elderly men, as indicated by AUC_inf to AUC_0-24 ratios of 1.31- and 1.50-fold, respectively.

Clinical observations. No serious adverse events were reported, and no subject discontinued from the study because of an adverse event. No age-related pattern in adverse events was observed, and the incidence of adverse events was comparable among young (56%, 10 of 18) and elderly (50%, 9 of 18) men. Most adverse events were mild in severity and considered related to treatment with dapoxetine. One adverse event, nausea in an elderly man, was rated severe, whereas another, headache in a young man, was rated moderate. The most frequently reported adverse event in both age groups was diarrhea (7 of 18 [39%] subjects in each group). Other adverse events reported in at least 2 subjects were abdominal pain, nausea, and headache. No clinically important changes in mean or individual laboratory values or vital signs were seen during the study, and there were no clinically important changes observed between the prestudy and poststudy ECGs.

View larger version (10K): [in this window] [in a new window]   Figure 2. Plasma concentrations of dapoxetine after a high-fat meal. Plasma concentrations of dapoxetine were measured after administration of dapoxetine 60 mg with and without a high-fat meal.

Dapoxetine pharmacokinetic analyses. Consumption of a standardized high-fat meal had a minimal impact on dapoxetine pharmacokinetics. Plasma dapoxetine concentration versus time curves for fed and fasted subjects are shown in Figure 2, and pharmacokinetic parameter values are summarized in Table II. Dapoxetine was rapidly absorbed and eliminated under both fed and fasted conditions. Maximum plasma concentrations were modestly decreased in the fed state compared to the fasted state (398 and 443 ng/mL, respectively) and were noted approximately 0.5 hours later (1.83 and 1.30 hours, respectively). However, this difference in t_max between the 2 treatments was not statistically significant (P = .1484, by Wilcoxon rank test). By 24 hours, plasma concentrations had decreased to approximately 5% of peak values in both fed and fasted states. The half-life of dapoxetine was not affected by the consumption of a high-fat meal.

The fed:fasted ratio of the least square mean values for the log-transformed pharmacokinetic parameters of dapoxetine indicated that the lower limit of the 90% CI for the fed:fasted lnC_max ratio was slightly outside the 80% to 125% no-effect boundary. The 90% CI for the fed:fasted lnAUC_inf ratio was within the 80% to 125% no-effect boundary.

Clinical observations. No serious adverse events were reported, and no subject discontinued from the study because of an adverse event. The rate of adverse events after administration of dapoxetine was 35% in the fed state (10 of 29) and 45% in the fasted state (13 of 29). All reported adverse events were rated mild or moderate in severity, and most were assessed as possibly related to treatment with dapoxetine. Nausea was the most commonly reported adverse event (7 of 29 [24%] in the fasted state and 4 of 29 [14%] in the fed state). Other adverse events reported in at least 2 subjects were headache, dizziness, and vomiting. There were no clinically important changes in laboratory values, vital signs, or ECGs during the study.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Dapoxetine has demonstrated efficacy for the treatment of PE when administered on demand, 1 to 3 hours prior to sexual activity.⁵ Unlike SSRI antidepressants, which have been used outside of their labeled indications to treat PE,⁴ dapoxetine has a pharmacokinetic profile characterized by rapid absorption and elimination, which are characteristics that may be desirable in a treatment for PE.⁷ The current studies have demonstrated that the pharmacokinetic profile of dapoxetine previously observed in young men is preserved in elderly men and that consumption of a high-fat meal has only a modest impact on the peak concentrations of dapoxetine.

Unlike ED, which is relatively rare in young men but moderately common in elderly men, PE is common in men of all ages^10,11; therefore, the pharmacokinetic profile, as well as the safety and efficacy profile, of pharmacologic agents used to treat PE must be understood in both young and elderly men. The clinical pharmacokinetics of various drugs have been studied extensively in the elderly, and age-related changes in pharmacokinetics have been found for many drugs, such as altered drug absorption, metabolism, distribution, or elimination.²⁰ An overall decline in metabolic activity has been observed in the elderly, and the clearance of creatinine is also altered.²¹ For example, some SSRI antidepressants exhibit altered pharmacokinetics in elderly men. In a study in which men received repeated daily doses of paroxetine (ranging from 20 to 40 mg), the trough plasma concentrations were 70% to 80% higher in young patients than in elderly patients.⁹ The AUC and half-life of citalopram after single doses were increased in elderly subjects by 30% and 50%, respectively.⁸ Fluoxetine pharmacokinetics were not altered in elderly patients.²² In contrast, dapoxetine was rapidly absorbed and eliminated in both young and elderly men, with no significant age-related differences. Maximal plasma concentrations of dapoxetine were noted approximately 1.3 hours after administration and decreased to less than 6% of peak concentrations by 24 hours.

The pharmacokinetics of a number of drugs are affected when coadministered with food, including antihistamines, theophylline, angiotensin converting enzyme (ACE) inhibitors, and some antibiotics.¹² Drug-food interactions are classified into 5 categories, based on the effect of food on absorption: those causing reduced, delayed, increased, or accelerated absorption, and those in which food has no effect.²³ Although SSRI antidepressants may be taken with or without food, their pharmacokinetics when taken with food may be altered to various degrees.^13-15 Peak plasma concentrations of paroxetine were increased by 29% and were noted 1.5 hours earlier when paroxetine was administered with food.¹³ Food does not affect the systemic bioavailability of fluoxetine, although food may delay its absorption by 1 to 2 hours.¹⁵ The AUC of sertraline was increased slightly when the drug was administered with food; the C_max of sertraline was 25% greater, whereas the t_max decreased from 8 hours to 5.5 hours.¹⁴ These changes in SSRI pharmacokinetics were not considered clinically important, nor did they require dose adjustments; however, each of these studies used different "fed" conditions. In contrast, consumption of a high-fat meal had only a minor effect on the pharmacokinetics of dapoxetine; mean peak dapoxetine concentrations were approximately 11% lower and occurred on average 30 minutes later following a high-fat meal, but the extent of absorption (ie, AUC) was not affected. The lower incidence of nausea among patients who received a high-fat meal may be related to the slowed rate of absorption and deserves further investigation.

	CONCLUSIONS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The pharmacokinetics of dapoxetine exhibited only minor differences between young and elderly men. In addition, consumption of a high-fat meal caused only modest changes in dapoxetine pharmacokinetics in healthy young men.

DOI: 10.1177/0091270006291033

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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