• Proceedings of the PSK Conference
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• 2003.04a
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• pp.315.1-315.1
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• 2003

After beginning the new medical system separating the prescription from the drug dispensary, the demand of bioequivalence test significantly increases to show the equivalence between the test and reference drugs as a result of amendment of the pharmaceutical affairs law which allows a generic substitution. Accordingly the standard protocols provided by the government are required for reducing the period andthe cost to perform the bioequivalence study. (omitted)

• Journal of Pharmaceutical Investigation
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• v.40 no.1
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• pp.63-66
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• 2010

The "Guidance Document for Bioequivalence Study" was revised for adding to bioequivalence studies of controlled-release products after meal(Korea Food & Drug Administration Notification #2008-22, 2008.5.7). The bioequivalence study design for controlled-release products is $2{\times}2$ crossover under fast and fed condition in respect. For studies of controlled-release products under fed study, the same high-fat diet should be taken within 20 minutes in at least a 10-hour fasting state. The drug products should be administered 30 minutes after the meal started. A high-fat(more than 35 percent of total caloric content of the meal) and high-calorie(over 900 calories) meal is recommended as a test meal for fed BE studies.

• Korean Journal of Clinical Pharmacy
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• v.19 no.1
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• pp.50-60
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• 2009

Highly variable drugs (within-subject variability greater than 30%) have been difficult to meet current regulatory acceptance criteria using a reasonable number of study subjects. In this study, we reviewed previous studies presenting alternative approaches for bioequivalence evaluation of highly variable drugs, and focused on an approach for widening the bioequivalence acceptance limits using within-subject variability. We discussed the suggested five solutions for highly variable drug including the deletion of $C_{max}$ of the bioequivalence criteria, direct expansion of bioequivalence limit, multiple dose studies in steady state, bioequivalence assessment on the metabolite, add-on study, and widening the bioequivalence acceptance limits based on reference variability. The methods for widening of bioequivalence limits based on reference variability are scaled average bioequivalence containing within-subject variability on reference drug (${\sigma}_{WR}$), population bioequivalence derived from total variability on reference drug (${\sigma}_{TR}$) and test drug (${\sigma}_{TT}$), and individual bioequivalence derived from subject by formulation interaction variability (${\sigma}_D$) and within subject variability on reference drug (${\sigma}_{WR}$) and test drug (${\sigma}_{TR}$). To apply these methods, the switching variability (${\sigma}_0$) will have to be set by the regulatory authorities. The proposals of bioequivalence evaluation approach for the highly variable in Korea are presented for both of new drug and reevaluation drug.

• Proceedings of the Korean Society of Toxicology Conference
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• 2006.11a
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• pp.80-86
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• 2006

Bioequivalence is a term in pharmacokinetics used to access the expected in vivo biological equivalence of two proprietary preparations of a drug. Bioequivalence studies are usually performed for generic drugs. Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilioes after administration in the same molar dose are similar. Bioequivalence is usually accessed by single dose in vivo studies in healthy volunteers and the reference product is usually the innovator product that is marketed. Regulatory definition of bioequivalence is based on the statistical analysis of thebioavailability of the reference and test product. In general, two products are evaluated as bioequivalent if the 90% confidence interval of the relative mean Cmaxand AUC of the test to reference product are within 80.00% to 125.00% in the fasting state. Key process in bioequivalence study is development and validation of bioanalytical method, determination of the drug concentration in the biosamples (usually plasma or serum) obtained from volunteers, calculation of the pharmacokinetic parameters and statistical analysis of the pharmacokinetic parameters. Although current guidelines and regulations do not require the bioequivalence studies to be done under good laboratory practice (CLP), the issues to perform the bioequivalence studies under GLP environment is emerged both from the regulatory and industry side. GLP perspectives of bioequivalence studiesare needed to be discussed in respect to achieve quality assurance in bioequivalence studies.

• 한국데이터정보과학회:학술대회논문집
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• 2006.11a
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• pp.43-48
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• 2006

In 2001 US FDA proposed a draft guidance for future in vivo bioequivalence studies. The guidance suggested specific criteria for new drug sponsors to show prescribability and switchability in bioequivalence testing for approval of generic drugs. However, there is less acceptance of the need to change statistical procedures and study designs from those currently used to assess the current criterion of average bioequivalence. The measures of population and individual bioequivalence testing are introduced and statistical procedures for them are discussed.

• Journal of the Korean Data and Information Science Society
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• v.18 no.3
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• pp.645-657
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• 2007

Several statistical procedures for assessment of bioequivalence of variabilities between two drug formulations in bioequivalence trials are reviewed and modified methods for assessing total variability are suggested. The problem of the current US FDA aggregate criterion for population bioequivalence and the necessity of disaggregate criterion are discussed with an illustrated example.

• YAKHAK HOEJI
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• v.44 no.4
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• pp.308-314
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• 2000

Logarithmic transformation of pharmacokinetic parameters is routinely used in bioequivalence studies based on pharmacokinetic and statistical grounds by the United States Food and Drug Administration (FDA), European Committee for Proprietary Medicinal Products (CPMP), and Japanese National Institute of Health and Science (NIHS). Although it has not yet been recommended by the Korea Food and Drug Administration (KFDA), its use is becoming increasingly necessary in order to harmonize with international standards. In the present study, statistical procedures for the analysis of a bioequivalence based on the log transformation and a related SAS procedure were demonstrated in order to aid the understanding and application. The AUC parameters used in this demonstration were taken from the previous bioequivalence study for two aceclofenac tablets, which were performed in a single-dose crossover design. Analysis of variance (ANOVA), statistical power to detect 20% difference between the tablets, minimum detectable difference and confidence intervals were all assessed following log-transformation of the data. Bioequivalence of two aceclofenac tablets was then estimated based on the guideline of FDA. Considering the international effort for harmaonization of guidelines for bioequivalence tests, this approach may require a further evaluation for a future adaptation in the Korea Guidelines of Bioequivalence Tests (KGBT).

• Journal of Pharmaceutical Investigation
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• v.35 no.5
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• pp.323-328
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• 2005

The purpose of the present study was to evaluate the bioequivalence of two torasemide tablets, Torem tablet (Roche Korea Co., Ltd., Korea, reference drug) and Boryung Torsemide tablet (Boryung Pharmaceutical Co., Ltd., Korea, test drug), according to the guidelines of Korea Food and Drug Administration (KFDA). After adding an internal standard (furosemide) to human serum, serum samples were extracted using 5 mL of ethyl acetate. Compounds were analyzed by reverse-phase HPLC method with UV detection. This method showed linear response over the concentration range of 0.05 ug/mL with correlation coefficient of 0.999. The lower limit of quantitation using 0.5 mL of serum was 0.05 ug/mL which was sensitive enough for pharmacokinetic studies. Twenty-eight healthy male Korean volunteers received each medicine at the torasemide dose of 20 mg in a $2{\times}2$ crossover study. There was a one-week washout period between the doses. Serum concentrations of torasemide were monitored by an HPLC-UV for over a period of 12 hr after the administration. $AUC_{t}$(the area under the serum concentration-time curve from time zero to 12 hr) was calculated by the linear trapezoidal rule method. $C_{max}$ (maximum serum drug concentration) and $T_{max}$ (time to reach $C_{max}$) were compiled from the serum concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_{t}$ and $C_{max}$. No significant sequence effect was found for all of the bioavailability parameters indicating that the crossover design was properly performed. The 90% confidence intervals of the $AUC_{t}$ ratio and the $C_{max}$ ratio for Boryung Torsemide/Torem were log 0.97-10g 1.03 and log 0.93log 1.12, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Boryung Torsemide tablet and Torem tablet are bioequivalent.

• The Korean Journal of Applied Statistics
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• v.24 no.6
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• pp.1055-1076
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• 2011

This paper reviews the definition of highly variable drug(HVD), the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence issues of HVD. The concept and the statistical approach of scaled average bioequivalence(SABE) is introduced and discussed with the current regulatory methods. The recommendations for SABE approach are proposed and the further study topics related to HVDs are also presented.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.420.1-420.1
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• 2002

The purposes of this study were to evaluate bioequivalence (BE) using In-transformed pharmacokinetic parameters obtained from two tiropramide HCI products and to develop the analytical methods for the quantitative determination of tiropramide in human serum. In addition. the in vitro dissolution profiles of the two tiropramide HCI products in various dissolution media: pH 1.2, 4.0. 6.8 and water (KP Ⅶ Apparatus II method) were assessed. BE was evaluated in 20 healthy male Korean volunteers in randomized crossover study. (omitted)