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Statistical Analysis System of Spontaneous Adverse Drug Reaction Reports.

Sira KIM ; Boram WANG ; Jungsun LEE ; Bori KIM ; Hyeno LA ; Young Min PARK ; Inyoung CHOI

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2012;20(2):155-164. doi:10.12793/jkscpt.2012.20.2.155

BACKGROUND: Spontaneous adverse drug reaction (ADR) reporting data has been used for safety of post-market drug surveillance. A system has been required that is able to detect signals associated with drugs by analyzing the collected ADR data. METHODS: We developed the web-based automated analysis system (ADR-detector). We used the data which reported ADR spontaneously between March 2009 and December 2010 to Korean Food and Drug Administration. We used 3 statistical indicators for evaluating ADR signals: proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). The ADR reports which were detected as significant signals based on the indicators have been reviewed. RESULTS: Among 153,774 reports, 9,955 cases were related to 4 analgesics which were most frequently reported analgesic drugs during the study period. The numbers of ADR reports associated with each drug are as follow: 5,623 reports in tramadol (56.5 %), 1,720 reports in fentanyl (17.3 %), 1,463 reports in tramadol-combination (14.7 %), and 1,149 reports in ketorolac (11.5 %). Top 5 ADR were nausea (3,351 reports - 33.7 %), vomiting (1,755 reports - 17.6 %), dizziness (1,130 - 11.4 %), rash (412 reports - 4.1 %), and pruritus (354 reports - 3.6 %). 6,674 ADR reports were significant based on PRR and ROR, and 336 reports were significant based on IC. CONCLUSION: By using the automated analysis system, not only statisticians but also general researchers are able to analyze ADR signals in real-time. Also ADR-detector would provide rapid review and cross-check of ADR.
Analgesics ; Data Mining ; Dizziness ; Drug Toxicity ; Exanthema ; Fentanyl ; Ketorolac ; Nausea ; Odds Ratio ; Pruritus ; Tramadol ; United States Food and Drug Administration ; Vomiting

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Bioequivalence and Dose Proportionality of Olmesartan Medoxomil Formulations.

Sung Kweon CHO ; Choon Ok KIM ; Su Hyun YU ; Eun Sil OH ; Seong Bok JANG ; Yoong Sik PARK ; Kyunghee CHO ; Jae Yong CHUNG

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2012;20(2):145-154. doi:10.12793/jkscpt.2012.20.2.145

BACKGROUND: Olmesartan medoxomil is an angiotensin II receptor blocker commonly used in hypertension. First objective of this study was to evaluate the bioequivalence of two olmesartan formulations, Olmesartan 20 mg and 40 mg tablet (Yuhan, Pharmaceutical Corp. Seoul, Korea) as test drugs and Olmetec(R) 20 mg and 40 mg tablet (Daewoong, Pharmaceutical Corp. Seoul, Korea) as reference drugs. Second objective of this study was to evaluate the dose-proportionality of two formulations. METHODS: Two studies (20 mg, 40 mg) were conducted as a randomized, open-label, 2-period, crossover design. Each subject received one 20 mg or 40 mg tablet of the reference or test formulation of olmesartan medoxomil in each study. Blood samples were obtained during the 48-hour period after the dose in each treatment period. Wash-out period was 1 week in each study. Concentrations of olmesartan medoxomil in plasma were analyzed using a liquid chromatography system with tandem mass-spectrometric detection (LC/MS/MS). The primary pharmacokinetic parameters were Cmax (maximum concentration) and AUCt (area under the concentration-time curve from time 0 to the last sampling time). RESULTS: A total number of 40 healthy male volunteers participated in the study and 37 volunteers completed both treatment periods in 20 mg trial. All 40 participants completed both treatment periods in 40 mg trial. The 90 % CIs for the geometric mean ratios of the pharmacokinetic parameters (test:reference drug) were 0.93 ~ 1.04 for AUCt and 0.97 ~ 1.08 for Cmax in 20 mg trial. The 90 CIs were 0.94 ~ 1.02 for AUCt and 1.00 ~ 1.11 for Cmax in 40 mg trial. All parameters of two studies satisfy the range of bioequivalence criterion. CONCLUSION: The obtained results indicated that pharmacokinetic exposure to Olmesartan 20 mg and 40 mg tablet was bioequivalent to that of Olmetec(R) 20 mg and 40 mg tablet, respectively.
Chromatography, Liquid ; Cross-Over Studies ; Humans ; Hypertension ; Imidazoles ; Male ; Plasma ; Receptors, Angiotensin ; Tetrazoles ; Therapeutic Equivalency

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Comparison of Pharmacokinetics and Safety of Two Formulations of Letrozole (2.5 mg) in Healthy Male Volunteers.

Yook Hwan NOH ; Kyun Seop BAE ; Sang Heon CHO ; Sangmin CHOE ; Jong Lyul GHIM ; Jin Ah JUNG ; Un Jib KIM ; Seok Joon JIN ; Hyun Jung PARK ; Jung Chul KIM ; Hyeong Seok LIM

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2012;20(2):135-144. doi:10.12793/jkscpt.2012.20.2.135

BACKGROUND: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. METHODS: This single-dose, randomized 2 x 2 crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. RESULTS: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of Cmax and AUClast were 0.92 (0.85 - 0.99) and 1.01 (0.97 - 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. CONCLUSION: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics.
Aromatase ; Breast ; Clinical Chemistry Tests ; Cross-Over Studies ; Electrocardiography ; Humans ; Male ; Nitriles ; Physical Examination ; Therapeutic Equivalency ; Triazoles ; Vital Signs

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Tolerability and Pharmacokinetics Following a Single Dose of Vardenafil in Healthy Korean Volunteers.

Seokuee KIM ; Seunghwan LEE ; Kyoung Soo LIM ; Hyeong Seok LIM ; Sang Goo SHIN ; In Jin JANG ; Kyung Sang YU

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2012;20(2):125-134. doi:10.12793/jkscpt.2012.20.2.125

BACKGROUND: Vardenafil is a phosphodiesterase type 5 inhibitor, used in erectile dysfunction. This study aimed to evaluate the pharmacokinetics and tolerability of vardenafil following a single oral administration in healthy male subjects. METHODS: A randomized, double-blind, placebo-controlled, single dosing, dose-escalation study was conducted in 30 healthy subjects. A single oral dose of vardenafil or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 5, 10 and 20 mg. Serial blood and urine samples were obtained up to 48 hours for pharmacokinetic analysis. Vardenafil and its metabolite were detected by high performance liquid chromatography tandem mass spectrometry assay. RESULTS: A total of 45 adverse events (AE) were reported in 22 subjects, including 5 AEs from placebo treatment, and all the AEs were mild, except one case of moderate nasal stuffiness. Vardenafil was absorbed after a single oral dose, with the tmax of 0.5-1.0 hours. The Cmax and AUClast were 10.21 +/- 3.68 ug/L(mean +/- SD) and 18.08 +/- 7.44 ugxh/L in 5 mg dose group, 19.79 +/- 12.13 ug/L and 38.61 +/- 21.04 ugxh/L in 10 mg dose group and 53.16 +/- 37.01 ug/L and 110.05 +/- 69.65 ugxh/L in 20 mg dose group. Dose-linearity on AUClast and Cmax of vardenafil were observed in three dose groups. In all dose groups, the fraction excreted in urine was less than 1%. CONCLUSION: The vardenafil was tolerable over a single dose range of 5 - 20 mg. The pharmacokinetics of vardenfil after a single oral dose was explored and linear pharmacokinetic characteristics were observed over the dose range of 5 - 20 mg in healthy subjects.
Administration, Oral ; Chromatography, Liquid ; Erectile Dysfunction ; Humans ; Imidazoles ; Male ; Piperazines ; Sulfones ; Tandem Mass Spectrometry ; Triazines

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A Review of Fundamentals of Statistical Concepts in Clinical Trials.

Kyungmee CHOI ; Jongtae LEE ; Sangil JEON ; Taegon HONG ; Jeongki PAEK ; Seunghoon HAN ; Dong Seok YIM

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2012;20(2):109-124. doi:10.12793/jkscpt.2012.20.2.109

Statistical analysts engaged in typical clinical trials often have to confront a tight schedule to finish massive statistical analyses specified in a Standard Operation Procedure (SOP). Thus, statisticians or not, most analysts would want to reuse or slightly modify existing programs. Since even a slight misapplication of statistical methods or techniques can easily drive a whole conclusion to a wrong direction, analysts should arm themselves with well organized statistical concepts in advance. This paper will review basic statistical concepts related to typical clinical trials. The number of variables and their measurement scales determine an appropriate method. Since most of the explanatory variables in clinical trials are designed beforehand, the main statistics we review for clinical trials include univariate data analysis, design of experiments, and categorical data analysis. Especially, if the response variable is binary or observations collected from a subject are correlated, the analysts should pay special attention to selecting an appropriate method. McNemar's test and multiple McNemar's test are respectively recommended for comparisons of proportions between correlated two samples or proportions among correlated multi-samples.
Appointments and Schedules ; Arm ; Chi-Square Distribution ; Cross-Over Studies ; Statistics as Topic ; Weights and Measures

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A Study on Current Status of Clinical Trial Pharmacy in Domestic Clinical Trial Institution.

Yoo Jeong JANG ; Wonku KANG ; Joomi LEE ; Hae Won LEE ; Min Soo PARK ; Young Ran YOON

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2013;21(1):71-81. doi:10.12793/jkscpt.2013.21.1.71

BACKGROUND: There is a lack of research on the status of clinical trial pharmacy and clinical trial pharmacist (CTP) in Korea. This study was aimed to investigate the current status of clinical trial pharmacy and clinical trial pharmacists. METHODS: The survey was performed using the 41-item questionnaire designed to investigate information on the following; (1) current status of clinical trial pharmacy designated by Korea Food and Drug Administration, (2) current status of working condition, management, and satisfaction index of CTP. Data collected was analyzed by t-test and chi2. RESULTS: Among the CTPs who responded, 92.7% belonged to department of pharmacy, and 7.3% to clinical trial center. 90.2% of the respondents were women. Forty-two point seven percents of the respondents had more than 3 years of experience in the clinical trial field. 36.6% answered that the current number of CTPs in the institution was '2'. Sixty-three point four percents answered that they subsumed an additional post. Regarding the question on "whether the equipment and working environment of your clinical trials pharmacy is adequate", 65.1% of the respondents answered as 'Inadequate'. Ninety-eight point eight percents answered that work-related education is needed. Ninety-three point nine percents answered that the quality of clinical trials is related to the improvement of the working environment of CTP. CONCLUSION: Clinical trial pharmacy's facility and number of actually working CTP were insufficient. Proper and continuous education and training for CTPs are needed to improve the quality of clinical trials conducted in Korea, with strong institution support and timely regulation change.
Cytidine Triphosphate ; Surveys and Questionnaires ; Female ; Humans ; Korea ; Pharmacists ; Pharmacy ; Silanes ; United States Food and Drug Administration

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A Placebo-Controlled, Single and Multiple Dose Study to Investigate the Appropriate Parameters for Evaluation of Pharmacodynamic Equivalence of Voglibose in Healthy Korean Volunteers.

Kyungho JANG ; Sang Heon CHO ; Jung Ryul KIM ; Jae Yong CHUNG ; Kyoung Soo LIM ; In Jin JANG ; Kyung Sang YU

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2013;21(1):63-70. doi:10.12793/jkscpt.2013.21.1.63

BACKGROUND: Voglibose is an alpha-glucosidase inhibitor. The purpose of this study was to evaluate the pharmacodynamic characteristics of voglibose for determining the appropriate study design and parameters for a pharmacodynamic equivalence study of voglibose. METHODS: This study consisted of two studies. The single dose study had an open and single sequence design. Nineteen subjects received placebo and then one tablet of voglibose on two consecutive days with sucrose. The multiple dose study was performed with the similar design, except that it was a multiple dose of the single dose study. Nine subjects who showed an effective response in the single dose study received placebo three times and then voglibose 4 times on two consecutive days. Serial blood samples for pharmacodynamic parameters were taken until 180 mins after each administration. The baseline adjusted maximum serum glucose level (G(max)) and area under the serum glucose level-time profiles were determined and compared. RESULTS: In the single dose study, the difference in G(max) was -10.6 +/- 28.7 mg/dL. The area under the serum glucose concentration-time curve (AUGC(0-1h)) of placebo and voglibose were 7825.0 +/- 1145.3 mg.min/dL, 7907.5 +/- 917.2 mg.min/dL, respectively. In the multiple dose study, the difference in G(max) was 46.6 +/- 16.1 mg/dL. The AUGC(0-1h) of placebo and voglibose were 8138.6 +/- 721.9 mg.min/dL and 6499.7 +/- 447.2 mg.min/dL, respectively. The G(max) and AUGC(0-1h) of the multiple dose study was significantly different between placebo and voglibose in paired t-test. CONCLUSION: The differences in G(max) and AUGC(0-1h) are suitable for pharmacodynamic parameters to evaluate bioequivalence of voglibose.
alpha-Glucosidases ; Glucose ; Inositol ; Sucrose ; Therapeutic Equivalency

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A Randomized, Placebo Controlled, Double Blind, Parallel Group, Multiple Dosing, Dose Escalation Clinical Study to Evaluate Pharmacokinetics/Pharmacodynamics and Tolerability of Zofenopril in Healthy Korean Subjects.

Jaeseong OH ; Seunghwan LEE ; Kyoung Soo LIM ; Jae Yong CHUNG ; Sang Goo SHIN ; In Jin JANG ; Kyung Sang YU

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2013;21(1):52-62. doi:10.12793/jkscpt.2013.21.1.52

BACKGROUND: Zofenopril is a new Angiotensin Converting Enzyme (ACE) inhibitor for the treatment of the patients with hypertension and congestive heart failure. This study aimed to evaluate the pharmacokinetics (PKs)/pharmacodynamics (PDs) and tolerability of zofenopril in healthy Korean subjects. METHODS: A randomized, double blind, placebo-controlled, multiple dosing parallel group study with two dosage groups (zofenopril 30 mg or 60 mg) was conducted in healthy Korean male subjects. Each dosage group consisted of 10 subjects and they were randomly assigned to receive zofenopril or placebo with a ratio of 4:1. PK characteristics of zofenopril and its active metabolite, zofenoprilat, were evaluated after single or multiple dosing. Serum ACE activities and blood pressures were measured for PD evaluation. Adverse events, clinical laboratory tests, electrocardiograms, vital signs and physical examinations were performed for tolerability evaluation. RESULTS: The PK characteristics of zofenopril and zofenoprilat after single dose and multiple doses were similar to one another. The metabolic ratio of zofenoprilat to zofenopril after single dose and multiple doses were 12.4 and 14.9, respectively, in the 30 mg dosage group, and were 6.8 and 6.6, respectively, in the 60 mg dosage group. Complete serum ACE activity inhibition was observed within 1 hour in both doses but it was maintained longer in the 60 mg dosage group compared to the 30 mg dosage group. There were no clinically significant abnormalities in tolerability evaluations. CONCLUSION: The PK/PD characteristics of zofenopril and zofenoprilat after single or multiple administrations were explored. Zofenopril was well tolerated after multiple administrations in healthy Korean subjects.
Captopril ; Electrocardiography ; Heart Failure ; Humans ; Hypertension ; Male ; Peptidyl-Dipeptidase A ; Physical Examination ; Vital Signs

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A Randomized, Open Label, 2-Way Crossover Study to Assess the Pharmacokinetic Characteristics and Skin Irritation of Murupe(R) Patch Compared with Trast(R) Patch in Healthy Volunteers.

Yoon Jung CHOI ; Young Mi KIM ; Jae Yong CHUNG ; Joo Youn CHO ; Kyung Sang YU ; In Jin JANG ; Kyoung Soo LIM

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2013;21(1):41-51. doi:10.12793/jkscpt.2013.21.1.41

BACKGROUND: A piroxicam patch has been widely used to treat musculoskeletal pain. The aim of this study was to assess the pharmacokinetic (PK) characteristics and skin irritation of Murupe(R) patch (piroxicam 96 mg) compared with Trast(R) patch (piroxicam 96 mg) in healthy volunteers. METHODS: A randomized, open-label, 2-way crossover study was conducted in 12 healthy Korean male subjects. They were allocated to one of the two treatment sequences of RT and TR (R, reference drug, Trast(R) patch; T, test drug, Murupe(R) patch). Each patch was applied to the subject once during 48 hours. Serial blood samples were collected up to 72 hours after removing the patch and plasma concentrations were determined by high performance liquid chromatography. Safety was monitored and the skin irritation potential was assessed. RESULTS: The plasma concentration-time profile during 48 hours showed an exponential increase in both of two patch products. Mean C(max) and AUC(last) values were not statistically different between two patch groups. Mean AUC[0-48h] was lower in Murupe(R) patch group than that in Trast(R) patch group; 806.4 and 1196.5 ng.h/mL. However, the mean AUC[48-120h] value tended to be higher in Murupe(R) patch group, implying more delayed excretion than in Trast(R) patch group; 2724.7 ng.h/mL and 1989.2 ng.h/mL. The overall results of skin irritation potential test showed no clinically significant differences between two patch groups. CONCLUSION: Mean Cmax and AUC(last) values in Murupe(R) patch group were comparable to those in Trast(R) patch group. Murupe(R) patch was safe and well tolerated in healthy male subjects.
Chromatography, Liquid ; Cross-Over Studies ; Humans ; Male ; Musculoskeletal Pain ; Piroxicam ; Plasma ; Skin

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Pharmacodynamic Comparison of Two Formulations of Voglibose 0.3-mg Tablet.

Mi Jo KIM ; Hyeong Seok LIM ; Sang Heon CHO ; Kyun Seop BAE

Journal of Korean Society for Clinical Pharmacology and Therapeutics.2013;21(1):34-40. doi:10.12793/jkscpt.2013.21.1.34

BACKGROUND: Voglibose, an inhibitor of alpha-glucosidase of the small intestine brush border, is used to treat type 2 diabetic patients. Bioequivalence test based on pharmacokinetic parameters is difficult because voglibose does not cross the enterocytes after ingestion. This study was conducted to establish bioequivalence of two formulations of 0.3-mg voglibose with pharmacodynamic endpoints. METHODS: This study was an open, single-dose, randomized, 6-sequence, 3-period crossover design in healthy volunteers. In each period, subjects received placebo or three tablets of either test formulation or reference formulation with sucrose, with a 7-day washout period each dosing period. Serial blood samples were collected after each administration. The maximum concentrations of serum glucose and serum insulin (C(max)(G) and C(max)(I)) and the area under the serum concentration - time curve from dosing to 2 or 4 hours after dosing for serum glucose and insulin (AUC(0-2h)(G), AUC(0-4h)(G), AUC(0-2h)(I) and AUC(0-4h)(I), respectively) were determined by noncompartmental analysis. Formulation-related differences were tested in accordance with the Korean regulatory bioequivalence criteria. RESULTS: A total of 54 subjects completed study in accordance with protocol. The geometric mean ratios (GMRs) of the test formulation to the reference formulation for Cmax(G), AUC(0-2h)(G), AUC(0-4h)(G), C(max)(I), AUC(0-2h)(I) and AUC(0-4h)(I) were 0.945, 1.014, 0.995, 0.937, 0.985 and 0.983, respectively and the 90% confidence intervals (CIs) of corresponding values were 0.985-1.026, 0.991-1.038, 0.977-1.014, 0.830-1.057, 0.901-1.078 and 0.911-1.014, respectively. CONCLUSION: This single-dose study found that two formulations of 0.3-mg voglibose did not meet the regulatory criteria for bioequivalence in these healthy volunteers.
alpha-Glucosidases ; Cross-Over Studies ; Eating ; Enterocytes ; Glucose ; Humans ; Inositol ; Insulin ; Intestine, Small ; Microvilli ; Sucrose ; Tablets ; Therapeutic Equivalency

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