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Several studies have reported that imatinib may induce tumor responses and prolonged disease stabilization in aggressive fibromatosis (AF). This effect may relate to the PDGFR-β pathway and KIT mutations. Sunitinib not only inhibits PDGFRs, KIT, and FLT3, it also blocks VEGFRs and thus serves as an antiangiogenic agent. The aim of this prospective multicenter uncontrolled study was to evaluate the efficacy and safety of sunitinib in patients with advanced AF. Nineteen patients with pathologically proven AF were recruited between June, 2008, and March, 2012, from three centers. One treatment cycle consisted of 37.5 mg/day sunitinib for 4 weeks without a break. The primary endpoint was tumor response rate according to RECIST 1.0. Ten (53 %) patients were female and the median age was 30 years (range, 22-67). Most of the primary sites were intra-abdominal (12, 63.2 %), and AF associated with familial adenomatous polyposis in ten patients (52.6 %). With a median of six cycles per patients (range, 1-47 cycles), five patients (26.3 %) achieved a partial response and eight (42.1 %) had stable disease. The overall response rate was 26.3 % (95 % confidence interval [CI], 6.3-45.7) in intention-to-treat analysis. With a median follow-up time of 20.3 months (range, 1.8-50.7), the 2-year rates of progression-free and overall survival were 74.7 % and 94.4 %, respectively. Grade 3 or 4 adverse events of sunitinib that occurred in >5 % of patients were neutropenia (33.3 %), diarrhea (5.3 %), and hand-foot syndrome (5.3 %). In 3 of 12 patients with mesenteric AF, mesenteric mass bleeding ( n = 1), bowel perforation ( n = 1), and bowel fistula ( n = 1) with tumor mass necrosis were observed early during sunitinib treatment. Therefore, sunitinib showed potential antitumor activity and may be useful for the management of non-mesenteric AF. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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) AUC0–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 AUC0−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. [Copyright &y& Elsevier]

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 Cmax with a median Tmax 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 Cmax and AUClast 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 AUClast 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 Cmax and AUClast 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 Cmax and AUClast 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. [Copyright &y& Elsevier]

Abstract: 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) AUC0−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. [Copyright &y& Elsevier]

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((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., 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((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., 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: 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-infinity) 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.

Background: LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation in Korea for the treatment of type 2 diabetes., Objective: The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects., Methods: A dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study was performed in healthy Korean male subjects assigned to receive 25, 50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected up to 72 hours after administration. Plasma and urine drug concentrations were determined by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP IV activity was measured by continuous spectrophotometric assay. An additional food effect study was performed in the 100-mg dose group; changes in PK and PD parameters after high-fat diet were evaluated. Adverse events (AEs) were detected through investigator inquiries, spontaneous reports, and clinical evaluations such as physical examinations, vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg, hematology, blood chemistry, coagulation, urinalysis), and computerized impedance cardiography., Results: Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range, 53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration, LC15-0444 reached T(max) at 0.5 to 5.1 hours, and was eliminated with a t((1/2)) of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444 =200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated. None of the subjects developed any serious clinical or laboratory AEs or discontinued the study due to an AE. All AEs were mild or moderate, and no dose-related trends were observed. Forty-six AEs were reported in 18 subjects (30.0%). AEs considered to be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis (1), and increased heart rate (1). All AEs resolved spontaneously., Conclusions: A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to 400 mg in these healthy Korean male subjects. PK characteristics were not significantly influenced by food. In addition, doses >or=200 mg of LC15-0444 inhibited plasma DPP IV activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally well tolerated.