• The Korean Journal of Applied Statistics
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• v.24 no.6
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• pp.1095-1102
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• 2011

The classical two-period, two-sequence crossover design is no longer sufficient to assess various demands in a bioequivalence study. For instance, to estimate the within-subject and between-subject variances of test and reference formulations separately, it is necessary to use a replicate design in which each subject receives at least the reference formulation in two periods. Several designs were studied to satisfy the demands. It is provided a unified Bayesian approach applicable to those study designs. The benefit of the method in the bioequivalence study is discussed.

• Communications for Statistical Applications and Methods
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• v.8 no.2
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• pp.443-452
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• 2001

The 2x3 cross-over design is proposed for the bioequivalence of two test drug formulations with a reference drug formulation. Oh et al.(1999) and Park et al.(1998) derived 3x2 cross-over design and discussed its benefits, since the 3x3 cross-over design may not be of practical design. We discuss the statistical issues for2x3 cross-over design and show its statistical properties. Bioequivalence problem in 2x3 cross-over design is considered statistically and an illustrated example is given.

• Journal of Pharmaceutical Investigation
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• v.38 no.5
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• pp.335-342
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• 2008

The bioequivalence of two carbamazepine preparations was conducted. The in vivo bioequivalence study in 20 healthy male Korean volunteers was designed by using a single dose, randomized, 2-period crossover with a 3-weeks washout period between the doses. Prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle and basket method as described in the bioequivalence guidance of the Korea Food and Drug Administration (KFDA). Based on the similar dissolution pattern between two preparations in the dissolution test, the two formulations are demonstrated to be pharmaceutically equivalent. In addition, in vivo bioequivalence test was used to reconfirm the in vitro dissolution results. In the in vivo bioequivalence study, the plasma concentrations of carbamazepine up to 144 h after the administration were determined using a validated HPLC method with UV detection and the bioequivalence between the two drug products was assessed by statistical analysis of the log transformed mean ratios of $C_{max}$, $AUC_{0-t}$ and $AUC_{0-\infty}$. The mean maximum concentration ($C_{max}$) of the test and reference were found to be $1467.0{\pm}335.8\;ng/mL$ and $1465.9{\pm}310.3\;ng/mL$, respectively. The 90% confidence intervals (C.I.) of $C_{max}$ were in the range from 0.95 to 1.05. As for the $AUC_{0-t}$ and $AUC_{0-\infty}$, test values were $110027.1{\pm}27786.4\;ng/mL{\cdpt}h$, $128807.0{\pm}34563.2\;ng/mL{\cdot}h$ and $105473.6{\pm}26496.2\;ng/mL{\cdot}h$, $125448.5{\pm}35975.5\;ng/mL{\cdot}h$, respectively. The 90% C.I. of $AUC_{0-t}$ were 0.97 to 1.10 and of $AUC_{0-\infty}$, 0.99 to 1.09 and thus were within the log 0.8-log 1.25 interval proposed by the KFDA. A two-way ANOVA showed no significant difference between the two formulations. Based on these statistical analysis, it was concluded that the test formulation is bioequivalent to the reference.

• YAKHAK HOEJI
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• v.51 no.6
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• pp.440-446
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• 2007

Arcabose is a competitive inhibitor of the intestinal ${\alpha}$-glucosidases and reduces the postprandial digestion and absorption of carbohydrate and disaccharides. Due to its negligible oral absorption, measuring drug concentration in the plasma is impractical. Thus, the common pharmacokinetic study is not available to determine the bioequivalence of the generic acarbose preparations. The aim of this study is the establishment of pharmacodynamic assessment method for the bioequivalence test of the generic acarbose preparations. Placebo-controlled cross-over ($3{\times}3$) clinical study was conducted in 23 healthy volunteers. Volunteers received a single oral dose of placebo, reference drug ($Glucoby^{(R)}$ 100 mg, Lot # D043) or test drug ($Glucoby^{(R)}$ 100 mg, Lot # E005) just before breakfast, then blood samples for evaluation of serum glucose and insulin levels were taken during for 4 hours. $C_{max},\;AUC_{0-2},\;AUC_{0-4},\;{\Delta}C_{max},\;{\Delta}AUC_{0-2}\;and\;{\Delta}AUC_{0-4}$ of the postprandial plasma glucose level significantly decreased when a single dose of acarbose 100 mg preparations was administered. However, any significant difference was not detected between the groups taken the reference drug and the test drug. These results proposed that the pharmacodynamic protocols of this study is suitable to use for bioequivalence test of acarbose preparations. On the basis of the results of this study and the data of literature on this subject, the standard protocols of bioequivalence study of acarbose preparation are proposed.

• 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.

• Journal of Pharmaceutical Investigation
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• v.24 no.2
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• pp.49-55
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• 1994

Bioequivalence test of commercially available rifampicin capsules was performed. Sixteen volunteers were divided into 2 groups and the reference and test drug were given orally (450 mg) by cross-over design. Statistical evaluation of AUC, $C_{max}\;and\;T_{max}$ involved an analysis of variance (ANOVA). The differences of mean value in AUC, $C_{max}\;and\;T_{max}$ between the reference and test drug were within 20% with reference drug. ANOVA showed no significant differences for ‘between group’, ‘drug’ and ‘period’, but not for ‘between subjects’. The power of test $(1-{\beta})\;of\;AUC\;and\;$C_{max}$ was larger than 0.8 and the confidence of bioavailability was $within\;{\pm}20%$. From these results, it was concluded that the two preparations were bioequivalent for AUC and $C_{max}$, but was not for $T_{max}$.

• Biomolecules & Therapeutics
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• v.6 no.4
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• pp.417-422
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• 1998

Loxoprofen sodium (sodium 2-[4-(2-oxocyclopentylmethyl)phenyl] propionate dehydrate) is a nonsteroidal antiinflammatory drug of $\alpha$-phenyl propionic acid derivative. To test the bioequivalence of loxoprofen, the pharmacokinetic parameters of new preparation of loxoprofen, LENOX was compared with LOXONIN as a reference drug. Fourteen healthy volunteers were entered to the stydy (Yonsei University College of Medicine, Severance Hospital IRB approval No. 9608). They were administered 60 mg of loxoprofen in 2$\times$2 cross-over design. There was one week of drug-free interval between doses. The blood sample was taken on schedule up to 8 hours, and the plasma concentration loxoprofen was measured by reverse phase high-performance liquid chromatography (HPLC) with UV-detector. There were no significant difference between two preparations when AUC, Cmax, and Tmax were compared by ANOVA. The mean differences of AUC, Cmax, and Tmax were within 20% of the reference drug: the values were 2.22,5.61, and 12.50%, respectively. The confidence limits of AUC and Cmax but not Tmax satisfied the bioequivalence criteria. These results suggest that the tested LENOX is bioequivalent to the reference drug.

• 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.

• Journal of Pharmaceutical Investigation
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• v.28 no.4
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• pp.223-229
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• 1998

A computer program for personal computers, $K-BEtest^{\circledR}$, was developed to analyze bioequivalence data in accordance with Korean Guidelines for Bioequivalence Test (KGBT). This program is user-friendly, interactive, Hangul-compatible and supports $2{\times}2$ cross-over design as well as $2{\times}2$ Latin square design with various significance levels. This program is able to calculate AUC, $C_{max}$ and $T_{max}$ parameters from the blood drug concentration-time profile of individual subjects and evaluate the parameters statistically for the bioequivalence by ${\pm}20%$ rule, the F-test, the Non-centrality test and 90% confidence intervals. All procedures are supported with graphic interface, interactive menu and outputs in Korean. In this paper, two experimental data sets were analyzed by the program and detailed process was demonstrated. The $K-BEtest^{\circledR}$ program appears to be very effective for analyzing bioequivalence data and can be widely used with convenience and accuracy.

• Journal of Pharmaceutical Investigation
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• v.28 no.1
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• pp.35-42
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• 1998

A $3{\times}3$ Latin square crossover study for the bioequivalence of three ondansetron formulations was conducted. Test products were $Vominon^{\circledR}$ 8 mg and $Vominon^{\circledR}$ 4 mg tablets and reference product was $Zofran^{\circledR}$ tablet. Twenty one healthy Korean male subjects received each formulation at the ondansetron dose of 8 mg and plasma concentrations of ondansetron were monitored by HPLC for over a period of 12 hr after the oral administration. Statistical procedure for bioequivalence evaluation of AUC {e.g., analysis of variance (ANOVA), multiple comparison and confidence intervals} was carried out. There were no significant differences in AUC among the formulations. The confidence intervals for the AUC of $Vominon^{\circledR}$ 8 mg and $Vominon^{\circledR}$ 4 mg were between -0.24 and 15.54% and between -2.41 and 13.36% respectively, within a range that proposed by the Korea Food and Drug Administration Guidelines for Bioequivalence. These statistical procedure could be standardized and generally applicable for the assessment of bioequivalence for multiple (more than two) formulations.