• 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)

• 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.

• Journal of Pharmaceutical Investigation
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• v.39 no.3
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• pp.217-219
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• 2009

There are several approaches to calculate a sample size for bioequivalence test. Among these approaches, sample sizes determination based on Schuirmann's two one-sided tests procedures has been used most popularly in case of 2${\times}$2 bioequivalence study. Here we proposed simple sample size table for conventional 2${\times}$2 bioequivalence test based on Schuirmann's two one-sided tests in accordance with Korean Guidelines for Bioequivalence Test. This table will allow researchers with a little statistical background to calculate the sample size for bioequivalence with easy process.

• Journal of the Korean Data and Information Science Society
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• v.17 no.1
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• pp.245-257
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• 2006

A modified Anderson and Hauck(1983) test for analyzing a two-sequence two-period crossover design in bioequivalence trials is proposed when some observations at the second period are missing. It is based on the maximum likelihood estimators of average bioequivalence model and designed for handling missing at random(MAR) situation. The performance of the proposed test is compared to other tests using Monte Carlo simulations.

• 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.

• YAKHAK HOEJI
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• v.54 no.4
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• pp.295-299
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• 2010

The aim of this study was to develop and validate for determination of alibendol in human plasma by HPLC method. After precipitation of 500 ${\mu}l$ plasma samples by 50% methanol 50 ${\mu}l$ and 60% perchloric acid 30 ${\mu}l$ and the supernatant 50 ${\mu}l$ was injected into HPLC. The assay was performed isocratically using 10 mM potassium phosphate (pH 3.0) and acetonitrile (80 : 20, v/v) as mobile phase. The $C_{18}$ column (particle size $3.5{\mu}m$, $4.6{\times}50$ mm, Zorbax Eclipse) was used as a solid phase. The mobile phase was delivered at a flow-rate of 1.7 ml/min, detection was by ultraviolet absorption at 232 nm and concentrations were calculated on the basis of peak areas. In these conditions, alibendol can be separated from ethylparaben, the internal standard, and endogenous substances. The retention times of alibendol and ethylparaben were just about 2.6 and 3.5 minutes, respectively. This rapid HPLC method was validated by examining the precision and accuracy for inter- and intra-day analysis. The standard curve was linear ($R^2$=1.0000) over the concentration range of 0.05~20 ${\mu}g$/ml. The inter-day relative standard deviation (R.S.D.) and accuracy were 0.2~12.2% and 94.4~101.2% (82.7% at the lower limit of quatitation). The intra-day R.S.D. and accuracy were 0.1~11.8% and 98.8~102.5%, respectively. The method was successfully applied to the determination of alibendol in plasma for a pharmacokinetic study.

• Journal of Pharmaceutical Investigation
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• v.19 no.4
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• pp.191-194
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• 1989

Bioequivalence test of $Asthcontin^{\circledR}$ tablet, a commercial slow-release theophylline (TP) dosage form, was performed using $Slo-bid^{\circledR}$ capsule as the reference. Since it has been confirmed that the saliva concentration of TP is closely correlated with the plasma concentration in man, the area under the saliva concentration-time curve was used as a bioavailability parameter. The statistical analysis showed that the two dosage forms are equivalent in bioavailability estimating from the saliva concentration. The results supported that the use of soliva as a test sample provides simple and easy techniques for bioequivalence tests of TP-containing dosage forms.

• Archives of Pharmacal Research
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• v.13 no.2
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• pp.180-186
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• 1990

A bioequivalence study of ranitidine tablets was conducted according to the Korean Guidine for the Bioequivalence Test using twelve healthy male subjects. The plasma concentration-timecurves of ranitidine from the test and reference tablets showed profound multiple peak phenomenon in each subject as reported earlier. However, the area under the plasma concentration-time curve (AUC) and the maximum ploasma concentration at the first peak ($C_{max1}$) of the two preparations was proven to be equal when analyzed satistically according to the criteria of the guidline;i. e., statistical power (1-$\beta$)was calculated to be over 0.8 under the condition of $\alpha$ = 5% and $\Delta$(minimum detectable difference) = 20%, and the confidence interval of the difference in AUC at 95% confidence level was in the range of $\pm$ 20%, which statisfied the criteria of bioequivalence. Equivalence of the peak concentration of ranitidine at the second peak ($C_{max2}$), and the time to reach the first ($T_{max1}$) and second verify the bioequivalence of $c_{max2}$ , $T_{max1}$ and $T_{max2}$ between the two tablets. However, we conclude that the test and reference tablets are bioequivalent taking the therapeutic characteristics of the ranitidine preparations into consideration.

• Communications for Statistical Applications and Methods
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• v.19 no.1
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• pp.47-55
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• 2012

The newly revised bioequivalence guideline of Korea allows the add-on test since July 1, 2008 when the initial bioequivalence trial fails to show the equivalence of two drugs. The statistical model of the add-on test and its two stage testing procedures are discussed. Some statistical points of consistency test in the add-on test are considered and the issue on the sample size of add-on test is discussed. Some reasonable alternative like Japan's guideline for bioequivalence studies is recommended to secure the proper use of an add-on study through some simulation studies.

• Proceedings of the Korean Statistical Society Conference
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• 2002.05a
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• pp.67-72
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• 2002

A Bayesian testing procedure is proposed for assessment of bioequivalence in both mean and variance which ensures population bioequivalence under normality assumption. We derive the joint posterior distribution of the means and variances in a standard 2 ${\times}$ 2 crossover experimental design and propose a Bayesian testing procedure for bioequivalence based on a Markov chain Monte Carlo methods. The proposed method is applied to a real data set.