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Purpose Rotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson's disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. Methods In this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. Findings A total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t ½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC 0–24h and C max values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. Implications The mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.

Fimasartan is an angiotensin II receptor antagonist used to treat hypertension.The aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements for drug marketing and labeling in Korea.An open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in healthy male volunteers. The subjects were administered a single-dose of warfarin 25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly with fimasartan. Serial blood samples were collected for 144 hours after each warfarin dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS, and the pharmacokinetic parameters were estimated by using noncompartmental analysis. The maximal international normalized ratio (INR) and the AUC-INR curve were evaluated to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements, physical examinations, ECGs, clinical laboratory tests, and adverse events.A total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years) and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed the study. The geometric mean ratios (GMRs [90% CIs]) of C(max) and AUC(0-last) for R-warfarin were 1.06 (0.97-1.16) and 1.07 (1.03-1.12), respectively. For S-warfarin, the GMRs (90% CIs) of C(max) and AUC(0-last) were 1.02 (0.94-1.11) and 0.99 (0.94-1.04). The INR values reached 1.93 (0.31) and 1.96 (0.37) at 36 hours and decreased to1.2 at 144 hours after warfarin treatment alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the maximal INR and AUC-INR curve were 1.01 (0.97-1.05) and 0.98 (0.96-1.01). One (7.7%) of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2 (16.7%) of 12 subjects receiving the combination treatment experienced headache, skin erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated INR4 or reported any symptoms related to hypotension, including fainting or dizziness.Multiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics of warfarin in this small, select population of healthy male volunteers.

Background Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population. Objective The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration. Methods A randomized, open-label, single ascending–dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin-corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements. Results Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median T max value in each of the 3 dose groups was 6.0 hours. Mean C max values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) μg/L; mean AUC 0–∞ values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) μg · h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments. Conclusions A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes—the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium—were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773.

Background: Recombinant human erythropoietin is indicated for the treatment of anemia resulting from chronic renal failure or chemotherapy. It is also used for patients at high risk for transfusions because of significant blood loss during surgery. A new recombinant human erythropoietin (epoetin alfa) that excludes fetal bovine serum and human serum albumin from among its ingredients was developed in Korea. This study was planned as part of a product development project at the request of the Korean regulatory agency. Objective: The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of a new recombinant human erythropoietin (test) formulation with an existing branded (reference) for- mulation after a single subcutaneous administration. Methods: An open-label, sequence-randomized, 2-period, 2-sequence, 2-treatment crossover study was conducted. Healthy male subjects were randomly assigned with a random number table into 1 of 2 sequence groups, and each subject was given recombinant human erythropoietin 4000 IU SC in the upper arm as the test formulation in one period and the reference formulation in the other period, according to the sequence group. Each period was separated by a 4-week washout period. Serial blood samples were taken up to 120 hours after drug administration for the pharmacokinetic assessments and up to 240 hours for reticulocyte counts as the pharmacodynamic end point. Pharmacokinetic analysis was performed without baseline correction. Adverse events (AEs) were collected by spontaneous reporting of the subjects or solicited by asking general health-related questions. Results: Twenty healthy men (mean [range] age, 25.6 [21–36] years; height, 175 [167–187] cm; weight, 70 [57.6–85.5] kg) were enrolled in and completed the study. The mean (SD) baseline erythropoietin plasma concentrations were 10.4 (2.4) mIU/mL for the test formulation and 10.8 (3.5) mIU/mL for the reference formulation. After the injection of 4000 IU SC per subject, the erythropoietin plasma concentrations reached a maximum at a median Tmax of 10 hours for both formulations (range: test formulation, 7.00–95.95 hours; reference formulation, 6.98–24.13 hours). The mean (SD) Cmax values for the test and reference formulations were 74.34 (30.63) and 80.46 (30.56) mIU/mL, respectively; the mean AUC0–last values were 3664 (731.5) and 3553 (723.2) mIU·h/mL. The ratios of the geometric mean (test/reference) for Cmax and AUC0–last were 0.92 (90% CI, 0.81–1.05) and 1.03 (90% CI, 0.98–1.09). The mean baseline hemoglobin, hematocrit, and reticulocyte counts were 15.4 g/dL, 45.5%, and 49.6 · 103/μL, respectively, for the test formulation and 15.5 g/dL, 45.3%, and 47.5 · 103/μL for the reference formulation. The mean reticulocyte counts slowly reached Tmax for both formulations at a median of 120 hours after administration (test formulation, 120.0 hours [range, 95.5–240.8 hours]; reference formulation, 120.1 hours [range, 72.0–240.5 hours]). The mean (SD) maximum reticulocyte counts for the test and reference formulations were 77.7 (12.2) · 103/μL and 80.7 (15.2) · 103/μL, respectively; values for area under the effect curve to the last observation (AUEC0–last) were 14,781.5 (2439.2) · 103/μL · h and 14,783.8 (2415.4) · 103/μL · h. The 2 agents did not exhibit any significant differences in maximum reticulocyte counts or AUEC0–last. During the study, a total of 6 AEs were reported, which were mild in severity. After the administration of test formulation, 1 case each of rhinorrhea, epigastric discomfort, and joint sprain (left ankle) were reported. After the administration of reference formulation, 2 cases of rhinorrhea and 1 case of cough were reported. Conclusion: In this small, selected group of healthy male volunteers, there were no significant differences in pharmacokinetic parameters or effects on reticulocytes between a test formulation and a reference formulation of recombinant human erythropoietin.

Objective: This study compared the bioavailability and tolerability of a fixed-dose combination (FDC) tablet of glimepiride/metformin 2/500 mg and glimepiride 2-mg + metformin 500-mg tablets administered separately in healthy Korean subjects. Methods: In this single-dose, open-label, 2-period crossover study, healthy Korean volunteers were randomly assigned to receive, in 1 of 2 randomized sequences, an FDC tablet of glimepiride/metformin 2/500 mg (test) and glimepiride 2-mg + metformin 500-mg tablets administered separately (reference), with a 1-week washout period between treatments. Plasma concentrations of glimepiride and metformin were measured using LC/MS-MS. Pharmacokinetic parameters were analyzed using noncompartmental methods. Bioequivalence was concluded if the 90% CIs of the geometric mean test/reference ratios (GMRs) of the logarithm-transformed C max , AUC from 0 to 30 hours (AUC 0–30 ), and AUC 0−∞ values were within the predetermined regulatory range of 80% to 125%. Tolerability was assessed using physical examination and laboratory analysis. Results: A total of 32 subjects were enrolled (16 men [mean (SD) age, 21.8 (2.7) years (range, 18–26 years); weight, 68.9 (8.3) kg (range, 55.5–85.0 kg)]; 16 women [age, 23.5 (4.5) years (range, 20–38 years); weight, 51.7 (3.5) kg (range, 46.8–58.0 kg)]). The GMRs (90% CI) of glimepiride C max , AUC 0–30 , and AUC 0−∞ were 1.01 (0.91–1.11), 0.98 (0.92–1.03), and 0.97 (0.93–1.04), respectively. For metformin, these values were 0.96 (0.87–1.06), 0.96 (0.90–1.03), and 0.96 (0.90–1.03). A total of 49 adverse events (AEs) were reported in 10 subjects (31.3%) with the FDC and in 13 subjects (40.6%) with the separate tablets. The most commonly reported AEs with the test and reference treatments were dizziness (6 [19%] and 7 [22%]) and sweating (4 [13%] and 7 [22%]), respectively. The severity of all of the AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. Conclusions: In this study in healthy Korean subjects, the requirements for bioequivalence of the glimepiride/metformin 2/500-mg FDC and coadministration of separate tablets of each drug were met. Both formulations were generally well tolerated.

Background: Coadministration 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. Objective: This 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. Methods: This 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. Results: A 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 t½ 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 · 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. Conclusions: The 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.

Background: Ticlopidine 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. Objective: To 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. Methods: An 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 ½ , AUC 0−∞ , 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. Results: Twenty-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 ½ 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–∞ , 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. Conclusion: Administration 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

Background: Mirodenafil is a phosphodiesterase type 5 (PDE-5) inhibitor developed for the treatment of erectile dysfunction. Mirodenafil has the possibility of being administered with alcohol. Objective: This study assessed the hemodynamic effects and pharmacokinetic properties of mirodenafil administered with alcohol. Methods: This 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. Results: A 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%]). Conclusions: The 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.

Flecainide 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.This study evaluated QTc-interval changes after administration of a single oral dose of flecainide, with and without paroxetine, in relation to CYP2D6 genetic polymorphism.This 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.Twenty-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], P0.001; 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], P0.001) 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], P0.001; and 5.8 milliseconds [90% CI, 3.4-8.3], P0.001). 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.The 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.

Background: Ginkgo biloba extract is an herbal medicine used in the treatment of vascular disorders that may be coadministered with antiplatelet agents such as ticlopidine. Regulatory authorities requested evaluation of the pharmacodynamic and pharmacokinetic interactions between these entities, according to the drug-development guidance for fixed-dose combination formulations in Korea. Objective: This study was performed to evaluate the potential pharmacodynamic and pharmacokinetic interactions between ticlopidine and Ginkgo biloba extract. Methods: An open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose crossover study was conducted in healthy Korean male volunteers. All volunteers were randomly assigned to a sequence group for the 2 treatments, which consisted of ticlopidine 250 mg alone and ticlopidine 250 mg with Ginkgo biloba extract 80 mg, separated by a 1-week washout period between the treatments. Bleeding time was determined just before dosing and at 5, 12, and 48 hours after dosing. Platelet aggregation was evaluated before dosing and at 4, 8, 26, and 48 hours after dosing. Blood samples (8 mL) from each of the volunteers were collected from an indwelling intravenous cannula inserted into a forearm vein before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after dosing. Ticlopidine concentrations were determined by a validated method using HPLC and ultraviolet detection. Adverse events were identified using general health-related questions, vital signs, physical examinations, ECGs, and laboratory tests. Results: A total of 24 healthy men participated in the study (mean [SD] age, 24.1 [4.3] years; weight, 66.6 [7.4] kg; height, 174.7 [5.0] cm). The baselinecorrected bleeding times were not significantly different between the ticlopidine-alone and ticlopidine/ Ginkgo biloba groups, and changes in platelet aggregation were not significantly different between the groups. Likewise, the pharmacokinetic parameters of ticlopidine were not significantly different between the groups; the geometric mean ratios of the ticlopidine/ Ginkgo biloba group to the ticlopidine-alone group were 1.03 (90% CI, 0.92–1.16) for C max , 1.08 (90% CI, 0.98–1.19) for AUC 0-last , and 1.10 (90% CI, 1.00–1.20) for AUC 0–∞ . A total of 28 adverse events were reported: 11 in the ticlopidine-alone group and 17 in the ticlopidine/ Ginkgo biloba group. The adverse events judged to be possibly related to ticlopidine in the ticlopidine-alone group were epigastric discomfort (2 cases), diarrhea (1), skin eruption (1), and a feeling of being cold (1) or hot (1). The adverse events judged to be related to ticlopidine or Ginkgo biloba in the ticlopidine/ Ginkgo biloba group were epigastric discomfort (2), diarrhea (2), nausea (2), and headache (1). Conclusions: In this small group of healthy Korean men, the addition of a single dose of Ginkgo biloba extract did not prolong the bleeding time and was not associated with additional antiplatelet effects compared with the administration of ticlopidine alone. The coadministration of Ginkgo biloba extract with ticlopidine was not associated with any significant changes in the pharmacokinetic profile of ticlopidine compared with ticlopidine administered alone.

Background: S -amlodipine gentisate, consisting entirely of the ( S )-enantiomer, was developed to increase the potency and improve the safety profile of amlodipine. Regulatory requirements for marketing of S -amlodipine gentisate in Korea require comparison of this agent versus amlodipine racemate. Objective: This study was conducted to compare the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of the S -amlodipine formulation ( S -amlodipine gentisate) and amlodipine racemate (amlodipine besylate). Methods: This study consisted of 2 separate substudies; PD and PK parameters were evaluated separately. Both studies were conducted using a doubleblind, randomized, 2-period, 2-treatment, 2-sequence, double-dummy, single-dose crossover design with S -amlodipine 5 mg and amlodipine racemate 10 mg, separated by a 2-week washout period. Blood pressure (BP) and heart rate were measured in the sitting position before dosing and at 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, and 72 hours after oral administration of S-amlodipine or amlodipine racemate. Impedance cardiography parameters (stroke volume, cardiac index, and systemic vascular resistance) were measured before and at 1, 2, 4, 5, 6, 7, 8, 10, and 12 hours after dosing. For PK assessments, serial blood samples were collected before dosing and at 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and drug concentrations were determined by HPLC-MS/MS. Adverse events (AEs) were collected using self-report or general health-related questions. Results: The PD study included 24 healthy men (mean [SD] age, 23.1 [3.1] years; weight, 69.2 [6.1] kg), and the PK study included 24 different healthy men (mean age, 25.1 [2.1] years; weight, 65.9 [5.9] kg). There were no statistically significant differences between the treatment groups in terms of systolic BP, diastolic BP, or heart rate by repeated-measures ANOVA. Likewise, in the analysis of impedance cardiography, the treatment groups did not display any significant differences in stroke volume, cardiac index, or systemic vascular resistance by repeatedmeasures ANOVA. The mean (SD) AUC 0–last was 129.7 (62.8) ng · h/mL after dosing with S -amlodipine and 129.0 (59.6) ng · h/mL after dosing with amlodipine racemate. The geometric mean ratio ( S -amlodipine: amlodipine racemate) of the S -amlodipine AUC 0−last was 1.01 (90% CI, 0.90–1.13). In the PD study, 4 AEs in 3 volunteers (3/24; 12.5%) and 8 AEs in 5 volunteers (5/24; 20.8%) were reported after dosing with S -amlodipine and amlodipine racemate, respectively. In the PK study, 18 AEs in 11 volunteers (11/24; 45.8%) and 20 AEs in 9 volunteers (9/24; 37.5%) were reported after dosing with S -amlodipine and amlodipine racemate, respectively. Five volunteers reported AEs after dosing with both S-amlodipine and amlodipine racemate. For the PD and PK studies combined, 30 AEs were judged to be possibly related to S -amlodipine (16 cases) or amlodipine racemate (14 cases). Twenty AEs were judged not to be related to S-amlodipine (6 cases) or amlodipine racemate (14 cases). The most common AEs considered at least possibly related to the study drug in both studies were headache (18 cases) and nausea (3 cases). Conclusions: In these single-dose studies, no significant differences were found in PD (hemodynamic) or PK parameters between S -amlodipine 5 mg and amlodipine racemate 10 mg. S -amlodipine had a safety profile comparable to that of amlodipine racemate in these healthy male volunteers.

Background: Bicalutamide is an oral nonsteroidal antiandrogen drug used during hormone ablation therapy for prostate cancer. A new generic formulation of bicalutamide has been developed. Objectives: This study was conducted to meet Korean and US regulatory requirements for the marketing of the generic 50-mg tablet formulation of bicalutamide. To this end, the pharmacokinetic properties of the new (test) formulation were compared with those of the currently marketed (reference) formulation. Tolerability was also evaluated. Methods: An open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy Korean male volunteers. Subjects received either the test or reference formulation of bicalutamide 50-mg tablets in the first period and crossed over to the alternative formulation in the second period. Serial blood samples for pharmacokinetic analysis were taken over 672 hours after dosing. Plasma concentrations of bicalutamide were measured by HPLC-MS/MS. Pharmacokinetic parameters, including AUC 0–672h , were determined by noncompartmental analysis. Log-transformed C max and AUC 0–672h for the 2 formulations were compared. Tolerability was monitored based on laboratory tests, ECGs, vital signs, and physical examinations. Results: Of the 34 subjects initially enrolled, 33 completed the study. The mean (SD) age, height, and weight of participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The median T max was 36.0 hours for both formulations. The mean (SD) t ½ , C max , and AUC 0–672h for the reference formulation were 135.4 (28.6) hours, 933.2 (169.2) μg/L, and 215,680.1 (48,753.4) μg · h/L, respectively. Corresponding values for the test formulation were 134.3 (30.7) hours, 946.7 (179.9) μg/L, and 221,708.8 (54,935.1) μg · h/L. The 90% CIs for the mean ratios (test/reference) of log-transformed C max and AUC 0–672h were 0.97 to 1.06 and 0.98 to 1.07, respectively. Twelve adverse events were reported for each formulation, none of which were considered drug related in the test-formulation group and 4 of which were considered drug related in the reference-formulation group (3 cases of headache, 1 case of erythematous rash). Conclusions: In this single-dose study in healthy Korean male subjects, the new formulation of bicalutamide 50-mg tablets met Korean and US regulatory criteria for assumption of bioequivalence with the currently marketed formulation. Both formulations were generally well tolerated, with no clinically relevant safety concerns.

Background: Mirodenafil, 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. Objective: The 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. Methods: An 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. Results: Nineteen 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−∞ ) 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 AUC0-X) 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). Conclusion: In these healthy Korean male volunteers, the coadministration of ketoconazole and rifampicin resulted in significant changes in systemic exposure to mirodenafil.

Background : Combined therapy with cilostazol, an antiplatelet agent, and probucol, an antihyperlipidemic agent, has been reported to prevent restenosis after percutaneous transluminal coronary angioplasty. However, the potential for pharmacokinetic drug interactions between the 2 agents has not been evaluated. Objectives : The aims of this study were to compare the pharmacokinetic properties of cilostazol and probucol administered alone and together in healthy Korean male volunteers. Methods : This open-label study in healthy adult (age 20–40 years) male volunteers consisted of 2 parts. Part A had a 1-sequence, 2-period crossover design in which each subject received cilostazol 100 mg (1 tablet) in period 1 and cilostazol 100 mg (1 tablet) plus probucol 500 mg (2 tablets) in period 2. Part B had a parallel-group design in which one group received probucol 250 mg (1 tablet) and the other received probucol 250 mg (1 tablet) and cilostazol 100 mg (1 tablet). Geometric mean ratios for C max and AUC were compared by ANOVA, and pharmacokinetic parameters were also compared by t tests. Tolerability was evaluated based on adverse events, ECGs, vital signs, and clinical laboratory test results. Results : Twelve healthy volunteers completed part A; their mean age was 24.1 years (range, 21–29 years), mean height 171.8 cm (range, 163–177 cm), and mean weight 65.2 kg (range, 56.3–77.6 kg). Of the 20 healthy volunteers enrolled in part B, 19 completed the study; their mean age was 25.1 years (range, 21–34 years), mean height 173.2 cm (range, 162–183 cm), and mean weight 65.5 kg (54.0–78.0 kg). The pharmacokinetic parameters of cilostazol and probucol did not differ significantly when the 2 agents were administrated alone or together. In part A, the geometric mean ratios for C max and AUC 0–60h between coadministration and single administration of cilostazol were 0.8882 (90% CI, 0.7873–1.002) and 1.013 (90% CI, 0.8643–1.188), respectively, for cilostazol; 0.8758 (90% CI, 0.7584–1.011) and 0.9785 (90% CI, 0.7600–1.260) for the OPC-13015 metabolite; and 0.8730 (90% CI, 0.7486–1.018) and 1.004 (90% CI, 0.8847–1.140) for the OPC-13213 metabolite. In part B, the geometric mean ratios for C max and AUC 0–648 h between coadministration and single administration of probucol were 1.134 (90% CI, 0.8177–1.572) and 1.070 (90% CI, 0.7364–1.555), respectively. Twenty-five adverse events were reported by 9 subjects in part A; the most frequently reported were headache (10 events) and nausea (4 events). Twenty adverse events were reported by 10 subjects in part B; the most frequently reported were headache (4 events) and productive cough (3 events). No clinically significant changes were noted in vital signs, ECGs, or laboratory values. Conclusion : In these healthy Korean male volunteers, coadministration of single doses of cilostazol and probucol had no significant effects on the pharmacokinetics of either drug. ClinicalTrials.gov identifier: NCT00549978

Background: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias. Objective: The objective of this study was to compare the pharmacokinetics and tolerability of pilsicainide in healthy Korean and Japanese male volunteers to satisfy regulatory requirements for marketing pilsicainide in the Republic of Korea. Methods: This was an open-label, single-dose, parallel-group, dose-increasing study. It was simultaneously conducted in healthy Korean and Japanese volunteers from September 2005 through May 2006; pilsicainide was approved for use in the Republic of Korea in 2007. Subjects for the 100-mg group were enrolled after the performance of tolerability evaluations in the 50-mg dose group. Serial blood and urine samples were collected up to 24 hours after dosing, and drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Tolerability was evaluated by monitoring adverse events (AEs), clinical laboratory parameters, and results of 12-lead electrocardiograms (ECGs). Results: Sixteen healthy Korean male subjects (mean [SD] age, 24.5 [4.2] years; weight, 71.8 [5.5] kg; height, 176.6 [6.3] cm) and 16 healthy male Japanese subjects (age, 24.7 [4.9] years; weight, 60.2 [4.4] kg; height, 171.9 [6.4] cm) were enrolled in the study. Values for AUC and C max of pilsicainide increased proportionally with dose escalation in all subjects. Pilsicainide reached C max 0.5 to 1.5 hours after dosing in both the Korean and Japanese subjects. The mean (SD) dose-normalized values for C max for the Korean and Japanese subjects were 9.4 (1.9) and 9.2 (1.6) ng/mL/mg, respectively. The mean (SD) dose-normalized values for AUC 0-∞ were 56.0 (8.0) ng · h/mL/mg in the Korean subjects and 53.8 (8.1) ng · h/mL/mg in the Japanese subjects. None of these findings were statistically significant. A total of 9 AEs occurred in 7 of the 16 Korean subjects; they included dizziness, feeling of being hot, somnolence, and atrioventricular block. All of the AEs were mild in severity and were considered possibly related to pilsicainide. Two of the 16 Japanese subjects had a total of 4 AEs. All of the AEs occurred in the subjects treated with 50 mg. Of the 2 subjects with AEs, 1 subject had a decrease in blood pressure, a sense of discomfort, and PR-interval prolongation on ECG, while the other developed a premature ventricular contraction (PVC). The PR-interval prolongation and PVC were determined to be possibly related to pilsicainide, and these were mild in severity. The other AEs (ie, decreased blood pressure, sense of discomfort) were moderate in severity. Conclusions: The results of this study suggest that the pharmacokinetic profile of pilsicainide was not significantly different between these healthy Korean and Japanese male volunteers. A single dose (50 or 100 mg) of pilsicainide was well tolerated in both ethnic groups.