JaeWoo Kim

Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects

AIMSnThe objectives were to evaluate the effect of CYP2D6 genetic polymorphism on the pharmacokinetics of flecainide, and also on the extent of drug interaction with paroxetine as a CYP2D6 inhibitor after a single oral administration in healthy subjects.nnnMETHODSnAn open-label, two-period, single-sequence, cross-over study was performed in 21 healthy Korean male volunteers (seven for CYP2D6*1/*1 or *1/*2, group 1; seven for CYP2D6*1/*10, group 2; seven for CYP2D6*10/*10 or *10/*36, group 3). Subjects were administered 200 mg of flecainide on day 1. After a 7-day wash-out period, subjects were administered 20 mg of paroxetine from day 8 to 14, and 200 mg of flecainide on day 15. Blood sampling was performed up to 72 h after flecainide administration.nnnRESULTSnTerminal elimination half-life and mean residence time (MRT) were significantly different among three genotype groups after a single oral administration of flecainide (P = 0.021, 0.011, respectively). Area under the concentration-time curve, terminal elimination half-life and MRT increased significantly after paroxetine co-administration only in groups 1 and 2.nnnCONCLUSIONSnThis study reports that the extent of drug interaction between flecainide and paroxetine is influenced by the CYP2D6*10 allele in healthy subjects, which is frequent in Asians.

Comparative Pharmacokinetics and Tolerability of Branded Etanercept (25 mg) and Its Biosimilar (25 mg): A Randomized, Open-Label, Single-Dose, Two-Sequence, Crossover Study in Healthy Korean Male Volunteers

BACKGROUNDnThe biosimilar is a recombinant dimeric tumor necrosis factor receptor (TNFR) under development for the treatment of rheumatoid arthritis.nnnOBJECTIVEnThe aim of this study was to compare the pharmacokinetics and/or tolerability of branded etanercept and its biosimilar in healthy Korean men before investigating the clinical efficacy of the biosimilar in subjects.nnnMETHODSnEtanercept (reference, 25 mg) or its biosimilar (test, 25 mg) was subcutaneously injected to the periumbilical area of healthy volunteers in a randomized, open-label, single-dose, active-controlled, two-sequence, crossover study. Plasma concentrations of TNFR in serial blood samples for 480 hours after dosing were measured by ELISA. The primary outcome, pharmacokinetic characteristics, was assessed via geometric mean ratios (GMRs) of the log-transformed pharmacokinetic parameters. The second outcome, tolerability, was evaluated using physical examinations, electrocardiograms, clinical laboratory tests, vital sign measurements, and adverse events (AEs) by unmasked investigators.nnnRESULTSnTwenty-three men of mean age (%CV) 25.8 years (17.1%) and weight 70.5 kg (12.8%) were administered study medication. Four subjects dropped out after the first period; their data were included in the analysis. Both test and reference drugs were absorbed with a median T(max) of 72 (range, 36-144) hours and eliminated with mean (%CV) t(½) of 92.7 (20.9%) and 87.4 (16.6%) hours, respectively. The GMRs (90% CIs) of the test to reference drug for C(max), AUC(0-t), and AUC(0-∞) were 0.99 (0.83-1.17), 0.95 (0.79-1.13), and 0.95 (0.80-1.13), respectively. Eleven of 21 (52.4%) and 8 of 21 (38.1%) subjects administered the test and reference drugs reported 22 and 21 AEs, respectively. Common AEs were headache (14.3%), throat irritation (8.5%), and epistaxis (9.5%). Three serious AEs related to a traffic accident (back, neck, and musculoskeletal pain) were reported in a test drug-treated subject.nnnCONCLUSIONSnIn this select group of Korean healthy male volunteers, the reference drug and the test biosimilar met the standard criteria for assuming bioequivalence as defined by Korean regulatory authorities. Because the reference drug is a biological product, further trials for assessment of its efficacy are still required by Korean authorities. World Health Organization International Clinical Trials Registry Platform identifier: KCT0000118.

Assessment of the drug-drug interactions between fimasartan and hydrochlorothiazide in healthy volunteers.

Aim Fimasartan is a selective angiotensin II receptor blocker. Hydrochlorothiazide (HCTZ), which is used to treat hypertension and edematous conditions, is coadministered with many antihypertensive agents. Methods An open-label, randomized, multiple-dosing, 2-arm, 1-sequence, 2-period study was conducted to assess the effects of fimasartan (240 mg) on HCTZ (25 mg) or vice versa in 18 and 14 healthy male volunteers, respectively. During each drug administration period, drugs were given once daily for 7 days, with a 7-day washout period between the 2 administration periods. Results The respective geometric mean ratios of fimasartan for AUC&tgr;,ss and Cmax,ss with HCTZ were 1.30 [90% confidence interval (CI), 0.84–2.01] and 1.17 (90% CI, 0.93–1.47) compared with fimasartan alone. The respective geometric mean ratios of HCTZ for AUC&tgr;,ss and Cmax,ss with fimasartan were 0.94 (90% CI, 0.84–1.04) and 0.88 (90% CI, 0.80–0.97) compared with HCTZ alone. Plasma renin activity indicated no significant differences between fimasartan monotherapy and coadministered treatment. Conclusions Fimasartan administered alone or in combination with HCTZ was well tolerated at the described dosages. Coadministration of fimasartan increased the urinary excretion of HCTZ and urine volume, but these observations are unlikely to have any clinical relevance.

Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: A single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea

BACKGROUNDnMirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol.nnnOBJECTIVEnThis study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol.nnnMETHODSnThis single-dose, randomized-sequence, open-label, crossover study was conducted in healthy male volunteers at the Clinical Trials Center, Seoul National University Hospital, Seoul, Korea. Volunteers were randomly allocated to 1 of 3 randomized-sequence groups, each of which consisted of 3 administration phases, each separated by a 1-week washout period: oral mirodenafil 100 mg, alcohol 0.5 g/kg, and both. Vital signs (systolic blood pressure [SBP], dia-stolic BP [DBP], and pulse rate) were measured before (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours after administration. Because volunteers were given a standardized meal at 4 hours after mirodenafil and/or alcohol administration, hemody-namic results were assessed using the maximum decrease from baseline during a period of up to 4 hours after administration. For pharmacokinetic assessment, serial blood samples were collected before (baseline) and at 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. Tolerability was assessed using monitoring of adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiography.nnnRESULTSnA total of 20 subjects participated in the study (mean [range] age, 25.5 years [20-41 years]; weight, 69.8 kg [57.4-87.2 kg]; and height, 174.7 cm [168-186 cm]). Up to 4 hours after the administration of mirodenafil, alcohol, and mirodenafil + alcohol, the mean (SD) maximum decreases in SBP were 8.5 (3.5), 13.5 (7.8), and 15.1 (6.7) mm Hg, respectively, and the maximum decreases in DBP were 6.4 (4.8), 13.3 (7.4), and 13.8 (5.2) mm Hg. Simultaneous administration of mirodenafil + alcohol was associated with additional mean (95% CI) decreases in SBP and DBP of 1.7 mm Hg (-6.0 to 2.6 mm Hg) and 0.6 mm Hg (-4.7 to 3.6 mm Hg) compared with alcohol alone. Pharmacokinetic parameters of mirodenafil were not significantly different when the drug was administered with or without alcohol. The mean (SD) AUC(0-t) values were 842.0 (434.7) ng/mL/h with mirodenafil and 833.4 (398.2) ng/mL/h with mirodenafil + alcohol. The most common AEs considered at least possibly related to study drug were nasal congestion (7 subjects [35%]), headache (3 [15%]), nausea (1 [5%]), and hiccups (1 [5%]).nnnCONCLUSIONSnThe concurrent administration of mirodenafil with alcohol was not associated with clinically significant hemodynamic changes in these healthy male volunteers in Korea. The pharmacoki-netics of mirodenafil were not significantly altered by this concurrent administration. Mirodenafil administered with alcohol had a tolerability profile comparable to that of mirodenafil alone.

Effects of Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix Extracts on Cytochrome P450 Activities in Healthy Volunteers

Three kinds of herbal medicines, commonly used in Korea, Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix were studied to evaluate their effect on cytochrome P450 (CYP) activities in healthy volunteers. A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05-0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54-0.94). In addition, S. radix showed a 1.42-fold (1.03-1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings.

The Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Mirodenafil in Healthy Korean Male Volunteers: An Open-Label, One-Sequence, Three-Period, Three-Treatment Crossover Study

BACKGROUNDnMirodenafil, a phosphodiesterase 5 inhibitor reported to be effective in the treatment of erectile dysfunction, is metabolized by cytochrome P450 (CYP) 3A4 to the active metabolite N-dehydroxyethyl mirodenafil. Mirodenafil may have drug-drug interactions with ketoconazole and/or rifampicin.nnnOBJECTIVEnThe aim of this study was to investigate the effects of a potent inhibitor (ketoconazole) and inducer (rifampicin) of the CYP3A4 isozyme on the pharmacokinetics of mirodenafil to meet the regulatory requirements for the marketing of mirodenafil in Korea.nnnMETHODSnAn open-label, 1-sequence, 3-period, 3-treatment crossover study was conducted over 22 days in healthy Korean male volunteers. Each subject received 100 mg of mirodenafil in each of 3 study periods: mirodenafil alone (period 1); mirodenafil after pretreatment with ketoconazole 400 mg once daily for 3 days (period 2); and mirodenafil after pretreatment with rifampicin 600 mg once daily for 10 days (period 3). Serial blood samples were collected for pharmacokinetic analysis after the administration of mirodenafil in each study period. Plasma concentration-time data for mirodenafil and its major metabolite, N-dehydroxyethyl mirodenafil, were determined using LC-MS/MS and analyzed by a noncompartmental method. The results for mirodenafil coadministration with either ketoconazole or rifampicin were compared with those for mirodenafil alone. Adverse events (AEs) were identified by asking general health-related questions of the subjects, by physical examination, and by subject self-report throughout the study period.nnnRESULTSnNineteen subjects were enrolled (mean [SD] age, 23.2 [2.76] years [range, 19-29 years]; weight, 69.3 [6.50] kg [range, 61.0-84.0 kg]; body mass index, 22.4 [1.77] kg/m(2) [range, 20.0-26.0 kg/m(2)]) and 18 subjects completed the study. One subject discontinued the study due to protocol violation and was replaced. The AUC(0-infinity) of mirodenafil increased 5.04-fold (90% CI, 3.78-6.72) and the metabolic ratio decreased 0.21-fold after pretreatment with ketoconazole compared with mirodenafil alone. After pretreatment with rifampicin, the AUC(0-infinity) of mirodenafil decreased 0.03-fold (90% CI, 0.02-0.05) and the metabolic ratio increased 2.9-fold. Twelve cases of headache, 6 of nasal congestion, 2 of feeling hot, 2 of epistaxis, and 1 each of dizziness, nausea, and somnolence were considered to be related to administration of mirodenafil. Twenty-eight AEs were reported in period 2 (in 68.4% of subjects), during which systemic exposure to mirodenafil was highest, whereas 7 AEs were reported in period 1 (in 31.6% of subjects) and 5 AEs in period 3 (in 16.7% of subjects).nnnCONCLUSIONnIn these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.

Changes in the QTc Interval After Administration of Flecainide Acetate, With and Without Coadministered Paroxetine, in Relation to Cytochrome P450 2D6 Genotype: Data From an Open-Label, Two-Period, Single-Sequence Crossover Study in Healthy Korean Male Subjects

BACKGROUNDnFlecainide acetate is a class Ic antiarrythmic agent that is metabolized by the cytochrome P450 (CYP) 2D6 isozyme. A previous open-label, 2-period, single-sequence crossover study in healthy Korean male volunteers found differences in the pharmacokinetics of flecainide between subjects with the CYP2D6 wild-type allele and those with the CYP2D6*10 allele, as well as differences in the pharmacokinetic interaction between flecainide and the CYP2D6 inhibitor paroxetine between genotype groups.nnnOBJECTIVEnThis study evaluated QTc-interval changes after administration of a single oral dose of flecainide, with and without paroxetine, in relation to CYP2D6 genetic polymorphism.nnnMETHODSnThis was a follow-on to the previous pharmacokinetic study and used data from the same group of healthy Korean male volunteers. Subjects were grouped by CYP2D6 genotype as follows: CYP2D6*1/*1 or CYP2D6*1/*2 (group 1, extensive metabolizers); CYP2D6*1/*10 (group 2, intermediate metabolizers); and CYP2D6*10/*010 or CYP2D6*10/*36 (group 3, poor metabolizers). Flecainide 200 mg was administered on day 1 (period 1); after a 7-day washout period, subjects received paroxetine 20 mg once daily from day 8 to day 14, and flecainide 200 mg on day 15 (period 2). On days 1 and 15, serial 12-lead ECGs were obtained before flecainide dosing and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. Baseline ECGs were obtained at the same time points on days -1 and 14. Machine-read changes in the QT interval corrected using the Fridericia formula (QTcF) and manually read changes in the QT interval individually corrected using mixed-effects modeling (QTcI) from time-matched baseline were analyzed by genotype and by period (baseline and paroxetine-inhibited state). The QRS duration and JTc interval (QTcF - QRS) were also determined.nnnRESULTSnTwenty-one healthy volunteers (mean [SD] age, 24.5 [3.0] years; mean height, 173.5 [4.6] cm; mean weight, 69.1 [4.5] kg), 7 in each group, were enrolled in and completed the study. In period 1, all genotype groups had significant increases from time-matched baseline in both the QTcF interval (group 1:17.4 milliseconds [90% CI, 9.9-24.9], P < 0.001; group 2: 11.1 milliseconds [90% CI, 7.9-14.3], P = 0.013; and group 3: 20.5 milliseconds [90% CI, 12.8-28.2], P < 0.001) and the QTcI interval (group 1:15.4 milliseconds [90 % CI, 8.0-22.9], P = 0.001; group 2: 9.1 milliseconds [90% CI, 6.5-11.8], P = 0.030; and group 3:16.4 milliseconds [90% CI, 9.3-23.5], P = 0.001); the extent of increase did not differ significantly between groups. In groups 1 and 2, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcF interval (6.5 milliseconds [90 CI, 3.2-9.8], P = 0.002; and 6.7 milliseconds [90% CI, 3.6-9.7], P = 0.001, respectively) and QTcI interval (6.9 milliseconds [90% CI, 4.1-9.8], P < 0.001; and 5.8 milliseconds [90% CI, 3.4-8.3], P < 0.001). In group 3, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcI interval (3.9 milliseconds [90% CI, 1.3-6.5], P = 0.015) but not for the change in QT cF interval. The changes in QRS duration did not differ significantly by genotype or period. Consistent with the findings for the QTc interval, the least squares mean difference between period 1 and period 2 was statistically significant for the change in JTc interval in groups 1 and 2 (6.9 milliseconds [90% CI, 3.7-10.2], P = 0.001; and 5.4 milliseconds [90% CI, 2.7-8.2], P = 0.001, respectively) but not in group 3.nnnCONCLUSIONnThe extent of drug interaction between flecainide and paroxetine, as reflected in the change in QTc interval (used as a pharmacodynamic biomarker), was influenced by the CYP2D6*10 allele in these healthy Korean male volunteers.

Pharmacokinetic Comparison of a New Glimepiride 1-mg + Metformin 500-mg Combination Tablet Formulation and a Glimepiride 2-mg + Metformin 500-mg Combination Tablet Formulation: A Single-Dose, Randomized, Open-Label, Two-Period, Two-Way Crossover Study in Healthy, Fasting Korean Male Volunteers

BACKGROUNDnCoadministration of glimepiride and metformin has been used to achieve glucose control. Because compliance with a multiple medication regimen can be difficult for some patients, combination tablets of glimepiride + metformin might be a suitable alternative for these patients.nnnOBJECTIVEnThis study was conducted to compare the pharmacokinetics of test and reference formulations of glimepiride + metformin fixed-dose combination tablets under fasting conditions to meet the regulatory requirements for marketing approval of a new drug in Korea.nnnMETHODSnThis was a single-dose, randomized, open-label, 2-period, 2-way crossover study conducted between March 2007 and May 2007. Healthy fasting Korean men were randomized to 1 of 2 dosing sequences: a single oral administration of a fixed-dose glimepiride 1-mg + metformin 500-mg combination tablet (test) followed by single oral administration of a fixed-dose glimepiride 2 mg + metformin 500 mg combination tablet (reference), separated by a 1-week washout period between doses; or a single oral administration of a fixed-dose glimepiride 2-mg + metformin 500-mg combination tablet followed by single oral administration of a fixed-dose glimepiride 1 mg + metformin 500-mg combination tablet, separated by a 1-week washout period between doses. Serial samples of blood were collected up to 24 hours after oral administration, and drug concentrations in plasma were determined by HPLC-MS/MS. Tolerability was assessed based on adverse events and changes in clinical parameters. Serious adverse events included those that resulted in death, a life-threatening condition, congenital anomaly or birth defect, or required hospitalization or prolongation of existing hospitalization.nnnRESULTSnA total of 30 healthy male subjects (mean age, 25.6 years [range, 20-36 years]; weight, 69.5 kg [range, 58.2-90.7 kg]) participated in the study. After administration of the test and reference formulations, glimepiride was rapidly absorbed, reaching C(max) with a median T(max) of 1.75 and 2.0 hours, respectively, and then declined exponentially with an average t(1/2) of 8.2 and 8.5 hours. The individual C(max) and AUC(last) of glimepiride were observed to be proportionally increased according to the administered glimepiride dose. The mean (SD) dose-normalized Cmax values of glimepiride 1 and 2 mg were 168.2 (54.9) and 149.9 (47.4) ng/mL/mg, respectively; the mean dose-normalized AUC(last) values of glimepiride 1 and 2 mg were 681.5 (190.3) and 635.8 (194.1) ng x h/mL/mg. Individual plots of dose-normalized C(max) and AUC(last) values identified a similarity between the 2 groups but no significant between-group differences. A total of 25 adverse events (12 after the test dose and 13 after the reference dose) were reported by 13 of the 30 subjects. All adverse events were considered mild. Twenty-one adverse events were considered related to the study drug (8 after the test dose and 13 after the reference dose). Adverse events believed to be related to the test formulation were diarrhea (4 cases), dizziness (1), headache (1), tingling sensation (1), and weakness (1). Adverse events believed to be related to the reference formulation were diarrhea (6 cases), headache (3), cold sweats (1), dyspepsia (1), epigastric discomfort (1), and lethargy (1). There were no clinically significant findings in the laboratory test results or vital sign monitoring during the study. There were no serious adverse events reported.nnnCONCLUSIONSnThe C(max) and AUC(last) of glimepiride increased proportionally according to the administered glimepiride dose in this study of healthy, fasting Korean men. The safety profiles of the 2 combination tablets were comparable.

Comparison of the pharmacokinetics of ticlopidine between administration of a combined fixed-dose tablet formulation of ticlopidine 250 mg/Ginkgo extract 80 mg, and concomitant administration of ticlopidine 250-mg and ginkgo extract 80-mg tablets: An open-label, two-treatment, single-dose, randomized-sequence crossover study in healthy Korean male volunteers

BACKGROUNDnTiclopidine is an antiplatelet agent used for the prevention of vascular accidents. In clinical practice in Korea, ginkgo extract may be administered along with ticlopidine to enhance the inhibition of platelet aggregation.nnnOBJECTIVEnTo meet the requirements for marketing a combined fixed-dose formulation in Korea, the investigators compared the pharmacokinetic characteristics of ticlopidine in a combined fixed-dose tablet of ticlopidine/ginkgo extract with the concomitant administration of ticlopidine and ginkgo extract tablets.nnnMETHODSnAn open-label, 2-period, 2-treatment, single-dose, randomized-sequence crossover study was conducted in healthy Korean male volunteers. Subjects were randomly allocated to 2 sequence groups. In one period, a combined ticlopidine 250 mg/ ginkgo extract 80-mg fixed-dose tablet was administered and, in the other period, ticlopidine 250-mg and ginkgo extract 80-mg tablets were concomitantly administered. A 7-day washout separated the 2 periods. For analysis of pharmacokinetic properties, including C(max), T(max), t((1/2)), AUC(0-infinity), and AUC(0-last), serial blood sampling was performed up to 48 hours after study drug administration during each period. Ticlopidine concentrations in plasma were determined by a validated method using LC-MS/MS. In order for the 2 treatments to be considered bioequivalent, the 90% CI of the geometric means ratios for C(max) and AUC needed to be between 80% and 125%. Bleeding time was determined before dosing (0 hour) and at 5 and 24 hours after dosing. Adverse events (AEs) were identified through patient interview, recording of blood pressure, heart rate, and body temperature, physical examination, 12-lead ECG, and laboratory assessments.nnnRESULTSnTwenty-four healthy Korean male subjects (mean [range] age, 23.9 [22-38] years; height, 174.0 [162-184] cm; weight, 67.4 [56-80] kg) completed the study. Median (range) T(max) of ticlopidine was 1.5 (0.5-2.0) hours in both groups. The mean (SD) t((1/2)) of ticlopidine in the combined fixed-dose formulation and the concomitant administration groups was 19.5 (3.4) and 19.0 (3.3) hours after study drug administration, respectively. The geometric means ratios of ticlopidine AUC(0-last), AUC(0-infinity), and C(max) between the combined fixed-dose formulation and concomitant administration were 1.04 (90% CI, 0.96-1.13), 1.04 (90% CI, 0.96-1.13), and 1.09 (90% CI, 0.96-1.23), respectively. The mean (SD) bleeding time at predose (0), and 5 and 24 hours after dose administration was 4.5 (1.6) to 5.4 (1.7) minutes in the combined fixed-dose formulation group and 4.4 (1.6) to 5.1 (1.1) minutes in the concomitant administration group. Five subjects (3 in the combined fixed-dose formulation group and 2 in the concomitant administration group) had bleeding times >8 minutes, but this was not considered to be clinically significant. A total of 24 AEs were reported in 13 of 24 subjects: nausea (3 cases), diarrhea (3), dizziness (3), epigastric discomfort (2), headache (2), rhinorrhea (2), purulent sputum (2), dyspepsia (1), upper abdominal pain (1), cough (1), pharyngolaryngeal pain (1), oropharyngeal swelling (1), dysphonia (1), and dysphagia (1). All were considered mild or moderate in nature. There was no statistically significant difference between the 2 treatments in the number of AEs or in the number of subjects who reported an AE.nnnCONCLUSIONnAdministration of a single dose of a combined fixed-dose formulation of ticlopidine 250 mg/ ginkgo extract 80-mg tablets and concomitant administration of ticlopidine and ginkgo extract tablets did not result in statistically significant differences in the pharmacokinetics of ticlopidine in these healthy Korean male volunteers.

Assessment of the effect of mirodenafil on the hemodynamics of healthy male Korean volunteers administered tamsulosin: a randomized, double-blind, placebo-controlled, 2-period crossover study.

BACKGROUNDnBoth mirodenafil, a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction, and tamsulosin, a selective α(1A)-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia, have mild vasodilational effects.nnnOBJECTIVEnThe aim of this study was to investigate the effect of mirodenafil on the hemodynamics of healthy volunteers who were administered tamsulosin.nnnMETHODSnHealthy, Korean normotensive male volunteers were enrolled in a randomized, placebo-controlled, double-blind, 2-sequence, 2-period crossover study. Mirodenafil 100 mg or placebo was administered orally after pretreatment with tamsulosin 0.2 mg once daily for 7 days in each period, with a 1-week washout period. Blood pressure (BP) and pulse rate (PR) in supine and standing positions were measured repeatedly before and until 24 hours after the administration of mirodenafil or placebo. The mean differences from the baseline values of the maximum changes of BP and PR, which were measured at 4 and 24 hours, were analyzed by using a mixed-effects model.nnnRESULTSnEighteen subjects (mean [SD] age, 26.8 [3.9] years; weight, 65.5 [7.0] kg) were administered any trial medication, and 16 of them completed the study. For 4 hours/24 hours after mirodenafil administration, the mean maximal changes from baseline versus placebo in supine systolic BP, diastolic BP, and PR were -1.0 mm Hg (95% CI, -4.2 to 2.2) (P = 0.53)/-1.2 mm Hg (95% CI, -5.3 to 2.9) (P = 0.56), -2.1 mm Hg (95% CI, -4.6 to 0.4) (P = 0.10)/-1.1 mm Hg (95% CI, -3.9 to 1.6) (P = 0.39), and 7.2 beats/min (95% CI, 4.7 to 9.6) (P < 0.05)/4.8 beats/min (95% CI, 1.4 to 8.1) (P < 0.05), respectively. Those changes in a standing position were -4.0 mm Hg (95% CI, -8.9 to 0.9) (P = 0.10)/-4.3 mm Hg (95% CI, -10.0 to 1.5) (P = 0.13), -1.1 mm Hg (95% CI, -4.9 to 2.7) (P = 0.54)/-1.9 mm Hg (95% CI, -5.5 to 1.7) (P = 0.27), and 10.7 beats/min (95% CI, 4.4 to 16.9) (P < 0.05)/6.0 beats/min (95% CI, 0.7 to 11.3) (P < 0.05), respectively. A total of 33 adverse events (AEs) were reported in 9 of 18 subjects. The number of subjects with AEs (P = 0.13) and the number of AEs (P = 0.26) were not significantly different between the 2 groups. The most common AEs were vasodilational symptoms, such as nasal congestion, headache, and flushing.nnnCONCLUSIONSnThe coadministration of mirodenafil 100 mg did not induce a significant decrease in BP when associated with an increase in PR in these healthy male Korean volunteers administered tamsulosin 0.2 mg compared with placebo. (Clinical Trial Registry, http://cris.cdc.go.kr/cris/en/: KCT0000117).