Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: A single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers

Clinical Therapeutics/Volume 32, Number 6, 2010

Tolerability and Pharmacokinetics of Avanafil, a Phosphodiesterase Type 5 Inhibitor: A Single- and Multiple-Dose, Double-Blind, Randomized, Placebo-Controlled, Dose-Escalation Study in Healthy Korean Male Volunteers Jinah Jung, MD1; Sangmin Choi, MD, PhD2; Sang Heon Cho, MD, PhD1; Jong-Lyul Ghim, MD, PhD3; Aekyung Hwang, MS1; Unjib Kim, MD1; Bong Sik Kim, MD4; Atsushi Koguchi, DVM, PhD5; Shinji Miyoshi, MS5; Hirotaka Okabe, MS5; Kyun-Seop Bae, MD, PhD1; and Hyeong-Seok Lim, MD, PhD1 1Department

of Clinical Pharmacology and Therapeutics, University of Ulsan, Asan Medical Center, Seoul, Korea; Trial Center, Pusan National University, Yangsan Hospital, Pusan, Korea; 3Clinical Trial Center, Yeungnam University, Daegu, Korea; 4Development Department, Medical Division, Choongwae Pharma Corporation, Seoul, Korea; and 5Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan 2Clinical

ABSTRACT Background: Avanafil is a selective phosphodiesterase type 5 inhibitor being developed for the treatment of erectile dysfunction. Objective: This study was conducted to meet Korean regulatory requirements for the marketing of avanafil. To this end, tolerability and pharmacokinetic properties of single and multiple oral doses of avanafil in healthy Korean male volunteers were assessed. Methods: A double-blind, randomized, placebocontrolled, parallel-group, dose-escalation study was conducted at the Asan Medical Center (Seoul, Korea). Subjects were randomized to receive either drug or placebo in blocks according to each dose. Subjects were randomly allocated to receive 50-, 100-, or 200-mg tablets of avanafil or placebo once daily for 7 days (avanafil:placebo, 8:2 in each dose group). Tolerability was assessed by monitoring vital signs and results of laboratory tests, 12-lead ECGs, and color discrimination tests. Blood samples of ~6 mL were collected in heparinized tubes before and 0.1, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration on days 1 and 7. Plasma concentrations of avanafil were measured using LC-MS/MS. Pharmacokinetic parameters of avanafil on days 1 and 7 were determined by noncompartmental analysis and compared among the 3 dose groups. Results: Of the 32 healthy male subjects initially enrolled, 30 completed the study. The mean (SD) age, height, 1178

and weight of the participants were 23.4 (1.7) years, 175.0 (5.4) cm, and 70.3 (8.9) kg, respectively. Adverse events were reported by 20 of 25 subjects (80%) taking avanafil and by 4 of 6 (67%) taking placebo. No serious adverse events were reported, and there were no clinically relevant changes in vital signs, ECG recordings, physical examination findings, or color discrimination test results. All the adverse events resolved spontaneously. Avanafil reached a mean Tmax at 0.33 to 0.52 hour after dosing and then declined, with a mean apparent t1/2 of 5.36 to 10.66 hours. AUC and Cmax were proportional to dose, and the mean accumulation index on day 7 after a single daily dose of avanafil was 0.98. Conclusion: Avanafil was generally well tolerated and had linear pharmacokinetic properties at daily doses of 50 to 200 mg over 7 days in these healthy Korean male volunteers. Korean National Study Registration Number: 3466. (Clin Ther. 2010;32:1178–1187) © 2010 Excerpta Medica Inc. Key words: avanafil, PDE5 inhibitor, pharmacokinetics, safety, Phase I.

Part of this research was presented as a poster at the 109th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, April 2–5, 2008, Orlando, Florida. Accepted for publication May 12, 2010. doi:10.1016/j.clinthera.2010.06.011 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.

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INTRODUCTION Erectile dysfunction (ED), defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance, is a condition that has a markedly negative impact on quality of life.1 It has been estimated that 10 to 30 million men in the United States and >100 million men worldwide experience some form of ED.2 The phosphodiesterase type 5 (PDE5) inhibitors vardenafil hydrochloride, tadalafil, and sildenafil citrate are recommended as first-line treatments for ED worldwide.3 PDE5 inhibitors enhance the relaxant effects of nitric oxide released in response to sexual stimulation by maintaining sufficient cellular levels of cyclic guanosine monophosphate in both the corpus cavernosum and the blood vessels supplying it.4,5 Increased dilatation of the corporal sinusoids occurs, allowing more blood flow, which induces an erection. Avanafil (4-[(3-chloro-4-methoxybenzyl) amino]-2-[2(hydroxymethyl)-1-pyrrolidinyl]-N- (2-pyrimidinylmethyl)5-pyrimidinecarboxamide) is a selective PDE5 inhibitor developed by Mitsubishi Tanabe Pharma Corporation (Osaka, Japan). Preclinical studies have reported that avanafil strongly inhibited PDE5 (half maximal inhibitory concentration, 5.2 nM) in a competitive manner.6,7 Avanafil had higher selectivity (120-fold) against PDE6 than sildenafil (16-fold) and vardenafil (21-fold), and high selectivity (>10,000-fold) against PDE1 compared with sildenafil (380-fold) and vardenafil (1000-fold); avanafil did not inhibit PDE11. Color vision disturbances are believed to be attributable to nonspecific inhibition of some PDE inhibitors, specifically PDE6.8,9 Two studies have evaluated the pharmacokinetics of avanafil in healthy male volunteers.10 Study 1 (N = 48) was a single- and multiple-dose trial of 50-, 100-, and 200-mg avanafil or placebo, and study 2 (N = 15) was a repeated-dose analysis with avanafil 200 mg BID for 7 days. Avanafil was well tolerated in these healthy volunteers, and the most commonly reported adverse events included headache, flushing, and nasal congestion. Mean Tmax was ~35 minutes. The present study was conducted to meet Korean regulatory requirements for the marketing of avanafil. To this end, tolerability and pharmacokinetic properties of single and multiple oral doses of avanafil in healthy Korean male volunteers were assessed.

SUBJECTS AND METHODS This was a double-blind, randomized, placebo-controlled, parallel-group, dose-escalation study at the Clinical June 2010

Pharmacology Research Unit, Asan Medical Center (Seoul, Korea). Subjects were randomized to receive either drug or placebo in blocks according to each dose. The clinical study protocols and written informedconsent forms were approved by the institutional review board of the Asan Medical Center. The study was conducted in compliance with the Korean Guideline of Good Clinical Practice11 and the ethical principles of the Declaration of Helsinki.12

Subjects After providing informed consent, volunteers were screened during the 3 weeks before the first dose. Healthy male volunteers, aged 18 to 45 years, weighing >45 kg and within ±20% of ideal body weight, were enrolled. Volunteers had to be in good health, as determined by assessment of their medical history, physical examination, 12-lead ECG, and results of visual color discrimination tests and laboratory tests (hematology, blood chemistry, and urinalysis). Laboratory tests were performed at the Department of Laboratory Medicine, Asan Medical Center, which was accredited by the Korean Association of Quality Assurance for Clinical Laboratories. Subjects were excluded if they had evidence of any clinically significant disease or abnormality (including drug hypersensitivity, allergy, or drug abuse) or if they had taken any prescription medication in the 2 weeks before the study; vitamins were permitted. Because visual disturbances have been reported with other PDE5 inhibitors,13 volunteers with a history of diabetic retinopathy or retinitis pigmentosa were excluded. Hematologic, cardiovascular, or psychological disorders, as well as acute illness, were also exclusion criteria.

Study Drug Administration All subjects were admitted to the Clinical Pharmacology Research Unit of the Asan Medical Center on the evening before the first day of drug administration and randomly assigned to 1 of the 3 dose groups (50, 100, or 200 mg). Each group consisted of 10 subjects; 8 received avanafil and 2 received placebo (all given as tablets). Investigators were blinded to the study treatment, and they assigned subjects using a predetermined randomization table provided by the sponsor. Investigators remained blinded throughout the study and were only made aware of treatment allocation when all data were ready for analysis. Beginning on day 1, subjects received the first dose of study drug or placebo with 240 mL of water; doses 1179

Clinical Therapeutics were thereafter administered at 24-hour intervals for 7 days. An indwelling angiocatheter was inserted into an antecubital vein for blood sampling. Before the collection of each blood sample, 1 mL of blood was drawn from the catheter and discarded. To ensure patency, 1 mL of sodium heparin (50 U/mL) was injected into the catheter after each blood sample was drawn. Blood samples of ~6 mL were collected in heparinized tubes before and 0.1, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration on days 1 and 7. Additional blood samples were drawn at 8:30 am on days 2, 3, 4, 5, and 6. Within 30 minutes of collection, blood samples were centrifuged at 1800g for 8 minutes at 4°C to separate plasma. Each plasma sample was immediately transferred to a polypropylene tube and stored at –70°C until analysis. Subjects were discharged from the clinical facility on day 8 and returned on day 13 for follow-up. Subjects for the next dose level were enrolled after safety data obtained at the lower dose had been reviewed by the investigator (who was blinded as to treatment group). Because PDE5 inhibitors are known to be metabolized by cytochrome P450 (CYP) 3A4,14 administration of CYP3A4 products (eg, those containing grapefruit) was not allowed beginning 14 days before the first dose and ending after the poststudy visit. Subjects were instructed to refrain from using other medications, consuming alcohol, or exercising more than 1 hour per day during the study.

Tolerability Assessments Tolerability assessments included monitoring for adverse events and analysis of laboratory test results (hematology, blood chemistry, and urinalysis), vital signs, 12-lead ECG, and color discrimination test results. Vital signs (blood pressure and heart rate) were measured before and at 0.5, 1, 2, 4, 8, and 12 hours after the first and last dose. Blood pressure was measured using an automated oscillometric device (Welch Allyn 520TP; Welch Allyn Inc., Skaneateles Falls, New York) while subjects were in a sitting position after a 5-minute rest. Twelve-lead resting ECGs were recorded using the MAC 5000 Resting ECG System (GE Healthcare, Milwaukee, Wisconsin) at baseline and 0.5, 1, 2, and 4 hours after administration. The QT interval values obtained by automatic measurement were corrected for heart rate using the Bazett formula,15 and other ECG parameters (heart rate, PR, QT, and QRS intervals) were also measured. Color discrimination was evaluated 1180

before and after dosing with the Farnsworth Munsell 100 Hue test; these results were processed with a computer program that plotted and scored the data.16 Adverse events were recorded by means of spontaneous reporting and specific questioning throughout the study period. They were defined as any new occurrence or worsening of a preexisting condition after administration of the study drug. To reduce bias, the nature and severity of all adverse events and the investigators’ assessment of the relationship between each adverse event and study drug were recorded while the investigators were blinded to the treatment group. A serious adverse event was defined as one that resulted in death, hospitalization, or persistent or significant disability, or was life threatening.

Pharmacokinetic Assessments In subjects who completed the study per protocol, the pharmacokinetic characteristics of avanafil were assessed by a noncompartmental method17 using WinNonlin version 5.1 (Pharsight Corporation, Mountain View, California). Cmax, Tmax, AUC0–24, AUC0–∞, apparent t1/2 (t1/2β), CL/F, volume of distribution at steady state, and volume of distribution based on the terminal phase were determined. The mean residence time (MRT) was calculated as the area under the moment curve divided by AUC. Effective t1/2 was estimated by the product of 0.693 and MRT. Also derived were a predicted accumulation index based on the AUC on day 1 and observed accumulation indices based on AUCs on days 1 and 7.

Analysis of Plasma Concentrations Determination of avanafil plasma concentrations was conducted at the Asan Medical Center Analytic Laboratory. Plasma concentrations of avanafil were determined by a sensitive and selective method using online solid-phase extraction (SPE) coupled to LC-MS/ MS; a triple quadrupole mass spectrometer was also used. Avanafil and an internal standard (IS [TA-1790 13C5 15N1 d2]) were provided by Choongwae Pharma Corporation (Seoul, Korea). Stock solutions of avanafil and the IS were prepared by dissolving 1 ng/mL of each in methanol. Twenty microliters of IS was added to each 200-μL aliquot of plasma, and the sample was transferred to an autosampler vial, which was inserted into the online SPE (Symbiosis; Spark Holland B.V., Emmen, the Netherlands) and LC-MS/MS system (API 4000; Applied Biosystems/MDX Sciex, Toronto, Ontario, Volume 32 Number 6

J. Jung et al. Canada) with Analyst 1.4 software (Applied Biosystems/ MDX Sciex). Chromatographic separation was conducted using a C18 column (Capcell Pak; Shiseido Co., Ltd., Tokyo, Japan; particle size, 3 μm; internal diameter, 2.0 × 50 mm). The mobile phase consisted of a mixture of 10-mM ammonium formate (pH 2.5) and acetonitrile (v/v, 65:35), with a flow rate of 0.3 mL/min and a column temperature of 30°C. The chromatographic run time was 5 minutes, and injection volume was optimized to 5 μL. The mass spectrometer with electrospray ionization source was operated in the positive mode. Quantitation was performed using multiple reaction monitoring of transitions of m/z 484.1 → 375.1 for avanafil and m/z 492.3 → 383.2 for IS. Avanafil concentrations were calculated from avanafil calibration curves, which were obtained by plotting the peak height ratio (avanafil ± IS) versus the concentration of avanafil in the calibration sample. The calibration standards were prepared at concentrations of 1, 2.5, 10, 25, 100, and 250 ng/mL from avanafil stock solutions at concentrations of 2000, 4000, and 8000 ng/mL. The equation was obtained by the least squares method using weighted linear regression with a weighting factor of 1/conc2, and the correlation coefficients of the calibration curves were ≥0.993 for avanafil. The lower limit of quantitation for avanafil was 1 ng/mL, and the limit of detection was 0.25 ng/mL. The intraday accuracy for avanafil 2, 20, 200, 2000, 4000, and 8000 ng/mL was 92.4%, 95.6%, 113.0%, 102.4%, 95.6%, and 96.2%, respectively; the corresponding intraday %CVs were 3.6%, 2.5%, 1.6%, 1.9%, 3.5%, and 2.3%. The interday accuracy was 91.9%, 96.3%, 109.2%, 104.8%, 95.3%, and 94.7%; the interday %CVs were 0.6%, 1.2%, 4.0%, 3.9%, 2.2%, and 4.0%. The assay was linear over the range

of 1 to 250 ng/mL, with dilution providing measurement up to 8000 ng/mL.

Statistical Analysis All statistical analyses were performed using SigmaStat 3.1 for Windows (Systat Software, Inc., Chicago, Illinois). Pharmacokinetic results were compared to determine any differences between days 1 and 7. P < 0.05 was considered statistically significant. Dose proportionality was assessed using the slope of ln(dose) for ln(AUClast), and declared if the 95% CIs for the slope included unity.18

RESULTS Subjects Of the 32 healthy male subjects initially enrolled, 30 completed the study. The mean (SD) age, height, and weight of the participants were 23.4 (1.7) years, 175.0 (5.4) cm, and 70.3 (8.9) kg, respectively. There were no significant differences in subject demographic characteristics among the 3 dose groups (Table I). One subject dropped out because of abnormal results on a visual color discrimination test taken before dosing; this subject was not included in any data analysis. The other subject was withdrawn because of an error in medication (the prescribed drug was different from that assigned). This subject was included only in the tolerability analysis. None of the other subjects had a medical history or findings that would adversely affect interpretation of the results.

Tolerability Adverse events were reported by 20 of 25 subjects (80%) taking avanafil and by 4 of 6 (67%) taking placebo. No serious adverse events were reported, and

Table I. Subject demographic characteristics. Data are given as mean (SD). Avanafil Group Characteristic Age, y Height, cm Weight, kg

50 mg (n = 9)

100 mg (n = 8)

200 mg (n = 8)

Placebo (n = 6)

Total (N = 31)

P*

23.0 (2.0) 176.5 (2.7) 71.9 (3.8)

24.0 (1.7) 173.8 (6.6) 66.8 (10.1)

23.0 (1.3) 175.7 (7.6) 73.5 (12.3)

23 (1.6) 173.6 (4.0) 68.7 (7.2)

23.4 (1.7) 175.0 (5.4) 70.3 (8.9)

0.61 0.48 0.43

*ANOVA.

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Clinical Therapeutics there was no clinically relevant change in vital signs, ECG recordings, physical examination findings, or color discrimination test results. The most commonly reported treatment-related adverse events were flushing, headache, and dizziness (Table II). Adverse events in the subjects who received avanafil included flushing, headache, dizziness, orbital pain, chest discomfort, epigastric heartburn, nasal congestion, erection, abdominal discomfort, chest discomfort, and paresthesia. Adverse events in the subjects who received placebo included flushing, headache, and dizziness. Abnormal laboratory findings are also summarized in Table II. Increases in blood bilirubin were <2 times the upper limit of normal. All adverse events were mild and resolved spontaneously.

Pharmacokinetics Avanafil reached a mean Tmax at 0.33 to 0.52 hour and then declined, with a mean t1/2β of 5.36 to 10.66 hours. Mean plasma concentration–time profiles for the avanafil groups are shown in Figure 1. Pharmacokinetic results of avanafil on days 1 and 7 are summarized in Table III.

In the dose range studied, there were no significant differences between pharmacokinetic results obtained on day 1 and those obtained on day 7. The mean accumulation index on day 7 after a single daily dose of avanafil was 0.98 (1.02 for 50 mg, 0.92 for 100 mg, and 0.99 for 200 mg). Figure 2 shows the distribution of Cmax and AUC0–24 after oral administration of single doses of avanafil ranging from 50 to 200 mg. Dose proportionality was observed, as the 95% CI for the slope of 1.14 (0.87–1.41) in the linear regression of ln(AUC) on ln(dose) included unity. There was no significant difference between the predicted and observed AUC values for subjects receiving avanafil 50, 100, or 200 mg (Table III). Therefore, time dependency of pharmacokinetics was not observed after once-daily dosing for 7 days.

DISCUSSION Submission of the results of the present study was delayed until the completion of the Phase III trial. In this group of healthy male volunteer subjects, avanafil was

Table II. Adverse events (including abnormal laboratory findings) after administration of avanafil. Data are given as number (%) of subjects. Avanafil Group Adverse Event

50 mg (n = 9)

100 mg (n = 8)

200 mg (n = 8)

Placebo (n = 6)

Adverse drug reaction* Flushing Headache Dizziness Epigastric heartburn Erection Nasal congestion Orbital pain Abdominal discomfort Chest discomfort Paresthesia Urine RBC increased Blood bilirubin increased Blood triglyceride increased Glucosuria Presence of ketone bodies in urine

9 (100) 9 (100) 2 (22) 2 (22) 1 (11) 1 (11) 0 0 0 0 0 1 (11) 0 0 0 0

7 (88) 6 (75) 3 (38) 1 (13) 0 0 1 (13) 1 (13) 1 (13) 0 1 (13) 0 1 (13) 1 (13) 0 0

4 (50) 2 (25) 3 (38) 1 (13) 0 0 1 (13) 1 (13) 0 1 (13) 0 0 0 0 1 0

4 (67) 1 (17) 2 (33) 1 (17) 0 0 0 0 0 0 0 1 (17) 1 (17) 0 0 1 (17)

RBC = red blood cell. *Adverse events that are possibly, probably, or definitely related to the drug.

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A

8000

Avanafil 50 mg Avanafil 100 mg Avanafil 200 mg

Concentration (ng/mL)

6000

4000

2000

0 0

6

12

18

24

162

168

Time (h)

Concentration (ng/mL)

B

6000

4000

2000

0 144

150

156

Time (h)

Figure 1. Mean (SD) plasma concentration–time profiles for avanafil at doses ranging from 50 to 200 mg on (A) day 1 and (B) day 7 in these healthy Korean male volunteers.

generally well tolerated at doses of 50 to 200 mg per day for 7 days. All adverse events were mild, and no treatment was required. Adverse-effect profiles of the other PDE5 inhibitors (sildenafil, vardenafil, and tadalafil) have been reported to be similar, with all having some propensity to cause headache, flushing, and nasal congestion, which are June 2010

likely to be related either directly or indirectly to their primary pharmacologic action.19 In the present study, however, these adverse events occurred with comparable high frequency in the avanafil and the placebo groups. This relatively high number of adverse events is in accordance with a previous report in young men which found that the rate of adverse events of sildenafil were 1183

Clinical Therapeutics

Table III. Pharmacokinetic parameters after administration of avanafil (n = 8 per dose group). Unless otherwise noted, values are given as mean (SD). Treatment Group Parameter

50 mg

100 mg

200 mg

Single-dose pharmacokinetics, day 1 Cmax, ng/mL Tmax, h* AUC0–24, h · ng/mL AUC0–∞, h · ng/mL t1/2β, h CL/F, mL/h Vz/F, mL MRT, h t1/2,eff, h

1206.00 (412.95) 0.33 (0.33–0.50) 2173.72 (794.86) 2217.22 (815.31) 5.36 (2.79) 0.025 (0.009) 0.178 (0.090) 2.76 (0.41) 1.91 (0.28)

2630.00 (747.83) 0.50 (0.33–1.00) 6838.30 (2247.59) 7148.67 (2430.31) 7.53 (3.23) 0.014 (0.005) 0.156 (0.093) 3.66 (0.78) 2.54 (0.54)

5161.25 (1675.75) 0.52 (0.33–0.83) 10867.03 (4009.16) 11610.16 (4245.44) 10.66 (6.21) 0.019 (0.008) 0.226 (0.145) 3.25 (0.70) 2.25 (0.48)

Steady-state pharmacokinetics, day 7 Cmax, ng/mL Tmax, h* AUC0–24, h · ng/mL AUC0–∞, h · ng/mL t1/2β, h CL/F, mL/h Vss/F, mL Vz/F, mL AIpred AIobs

1159.13 (476.71) 0.50 (0.50–0.50) 2280.61 (856.07) 2524.94 (1090.29) 10.08 (6.54) 0.018 (0.008) 0.058 (0.02) 0.169 (0.068) 1.04 (0.03) 1.02 (0.11)

2231.63 (1091.82) 0.42 (0.33–0.75) 6222.30 (3620.79) 7339.13 (4815.90) 8.66 (4.85) 0.013 (0.006) 0.059 (0.02) 0.185 (0.098) 1.04 (0.02) 0.92 (0.35)

3992.50 (1524.84) 0.50 (0.33–1.00) 10,328.17 (2118.65) 11,246.21 (1870.39) 9.97 (5.17) 0.014 (0.004) 0.076 (0.02) 0.157 (0.062) 1.06 (0.04) 0.99 (0.21)

t1/2β = apparent t1/2; Vz/F = volume of distribution based on the terminal phase; MRT = mean residence time; t1/2,eff = 0.693 · MRT; Vss/F = volume of distribution at steady state; AIpred = predicted accumulation index; AIobs = observed accumulation index. *Median (range).

higher than in an older population.20 In addition, the frequency of these adverse reactions was thought to be partly attributable to the fact that attention (mainly media reports) had been directed to the adverse effects of the drug. Although transient impairment of color discrimination (blue/green) has also been reported for the other PDE5 inhibitors,21 no abnormality in color discrimination (“blue vision”) after administration in either the avanafil or placebo groups was observed in the present study. In East Asian countries, including Korea, Japan, and Singapore, adverse-event rates are reportedly higher in men taking sildenafil 100 mg than in those prescribed 50 mg.22 In all, 100-mg sildenafil led to an increase of adverse events such as blurred vision in 11.1%, com1184

pared with 2.2% for the 50-mg dose. In Japan, the approved maximum drug dose is 50 mg, as a clinical trial failed to demonstrate any superiority of 100 mg compared with 50 mg.23 After oral administration of 100 mg of sildenafil, plasma concentrations of the drug and that of its active metabolite (UK-103,320) were higher in Korean subjects than in white subjects. Cmax of sildenafil 50 mg and the ratio of Cmax sildenafil/ UK-103,320 (419 ng/mL and 4.9, respectively) in Korean subjects24 were higher than those reported by Nichols et al25 (271 ng/mL and 2.2) and Walker et al26 (212 ng/mL and 2.1). Similarly, avanafil plasma concentration values appeared to be higher in the Korean subjects from the present study compared with those values previously reported for white subjects.10 Cmax of avanafil in Korean Volume 32 Number 6

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8000

Cmax (ng/mL)

6000

4000

2000

0 0

50

100

150

200

150

200

Dose (mg)

AUC0–24




B

15,000

10,000

5000

0 0

50

100

Dose (mg)

Figure 2. Relationship between the extent of systemic exposure after oral administration of single doses of avanafil ranging from 50 to 200 mg in healthy Korean male volunteers. The filled circles are the individual observed values; the solid lines are the fitted values based on the linear regression, and the dashed lines are the 95% CIs. (A) Cmax and (B) AUC0–24.

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Clinical Therapeutics subjects (N = 8) and that of white subjects (N = 12) were 1206 and 686 ng/mL, respectively. Any interpretation should be made cautiously, however, because inclusion/ exclusion criteria, method to determine plasma concentration, and time points of blood sampling can lead to different pharmacokinetic results. The reason for this discrepancy and any relationship thereof to adverseevent rates require further evaluation. The findings of this study should be considered within the context of the study limitations. First, our population included only healthy male volunteers who lived in Korea; the results are therefore difficult to extrapolate to the general patient population. Second, despite the fact that a modest number of subjects per treatment group is usually acceptable for Phase I trials, the sample size of the present study was relatively small. Further clinical investigation of the efficacy of avanafil in the treatment of ED is therefore warranted.

CONCLUSION Avanafil was generally well tolerated and had linear pharmacokinetic properties at daily doses of 50 to 200 mg over 7 days in these healthy Korean male volunteers.

ACKNOWLEDGMENTS The research and publication of this article were sponsored by Choongwae Pharma Corporation. The sponsor had no part in the study design or in the collection, analysis, or interpretation of the data. Drs. Jung and Bae wrote the manuscript; Drs. Choi, Cho, Ghim, U. Kim, and Lim participated as investigators and reviewed the manuscript; and Drs. B.S. Kim and Koguchi, Mr. Miyoshi, and Mr. Okabe reviewed and revised the manuscript. Ms. Hwang measured the plasma concentrations of avanafil. The authors have indicated that they have no conflicts of interest regarding the content of this article. The authors are grateful to Jeong Hyun Yoon, PharmD, senior staff member of the clinical research team at Choongwae Pharma, for her assistance with study monitoring.

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4. Francis SH, Corbin JD. Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep. 2003;4:457–465. 5. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract. 2002;56:453–459. 6. Palmer MJ, Bell AS, Fox DN, Brown DG. Design of second generation phosphodiesterase 5 inhibitors. Curr Top Med Chem. 2007;7:405–419. 7. Beavo JA. Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol Rev. 1995; 75:725–748. 8. Omori KM, Fujishige K. Avanafil has the potential for the treatment of erectile dysfunction with selective phosphodiesterase-5. J Sex Med. 2006;3(Suppl 3):221–222. 9. Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunction: Which treatment for which patient? Drugs. 2005;65:1621– 1650. 10. Peterson CS. Pharmacokinetics of avanafil, a new PDE5 inhibitor being developed for erectile dysfunction. J Sex Med. 2006;3(Suppl 3):253–254. 11. Korea Food and Drug Administration. Korea good clinical practice (KGCP) guidelines. http://clinical trials.kfda. go.kr/guide/laws/board_list.jsp?category_seq=12. Accessed March 31, 2010. 12. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA. 2000;284:3043–3045. 13. Gonzalez CM, Bervig T, Podlasek C, et al. Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina. Int J Impot Res. 1999;11(Suppl 1):S9–S14. 14. Arayne MS, Sultana N, Bibi Z. Grape fruit juice-drug interactions. Pak J Pharm Sci. 2005;18:45–57. 15. Bazett H. An analysis of the time-relations of the electrocardiograms. Heart. 1920;7:353–376. 16. Franklin A, Sowden P, Notman L, et al. Reduced chromatic discrimination in children with autism spectrum disorders. Dev Sci. 2010;13:188–200. 17. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications. 3rd ed. Baltimore, Md: Williams & Wilkins; 1995:70, 485. 18. Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 2000;17:1278–1283. 19. Mehrotra N, Gupta M, Kovar A, Meibohm B. The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. Int J Impot Res. 2007;19:253–264. 20. Dündar M, Koçak I, Dündar SO, Erol H. Evaluation of side effects of sildenafil in group of young healthy volunteers. Int Urol Nephrol. 2001;32:705–708. 21. Viagra (sildenafil citrate) [prescribing information]. Description, clinical pharmacology, adverse reactions. Pfizer

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Address correspondence to: Kyun-Seop Bae, MD, PhD, Department of Clinical Pharmacology and Therapeutics, University of Ulsan, Asan Medical Center, 388-1 Pungnap-dong Songpa-gu, Seoul, 138-736, Republic of Korea. E-mail: [email protected] June 2010

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