• Journal of Pharmaceutical Investigation
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• 제39권6호
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• pp.451-456
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• 2009

The purpose of the present study was to evaluate the bioequivalence of two ciprofloxacin tablets, Ciprobay (Bayer Korea Ltd.) and Rofcin (Binex Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The release of ciprofloxacin from the two ciprofloxacin tablets in vitro was tested using KP XIII Apparatus I method with dissolution media (0.01 M HCl). The dissolution profiles of two ciprofloxacin tablets were very similar at dissolution media. Twenty four healthy male volunteers were divided into two groups and a randomized 2$2{\times}2$2 cross-over study was employed. After one tablet (250 mg ciprofloxacin) was orally administrated, blood was taken and the concentrations of ciprofloxacin in serum were determined using HPLC with UV detector. The pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two ciprofloxacin tablets based on the Ciprobay were -0.63%, 3.98% and -9.23%, respectively. There were no sequence effects between two tablets in these parameter. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25)(e.g., log(0.9520)~log(1.0523) and log(0.9689)~log(1.1663) for $AUC_1\;and\;C_{max}$, respectively). Thus, Rofcin tablet was bioequivalent to Ciprobay tablet.

• 약학회지
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• 제48권6호
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• pp.379-383
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• 2004

Biphenyl dimethyl dicarboxylate (DDB) has been used for the treatment of chronic viral hepatitis B and drug-induced hepatitis through the inhibition of lipid peroxidation and c ovalent binding of drug metabolites to lipids of microsomes. The bioequivalence of two DDB products was evaluated according to the guidelines of KFDA. The test product was Hepaphil soft capsule(R) made by KMS Pharm. Co. Containing 3 mg DDB and the reference product was Nissel tablet(R) made by Taerim Pharm. Co. Containing 25 mg DDB. Twenty healthy male subjects, 25.4(22~30) years old and 66.7(54~77)kg, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After two tablets or two capsules were orally administered, blood was taken at predetermined time intervals and the concentration of DDB in plasma was determined using a validated HPLC method with UV detector. Two pharmacokinetic parameters, $AUC_t$ and $C_{max}$, were calculated and analyzed statistically for the evaluation of bioequivalence of the two products. Analysis of variance was carried out using logarithmically transformed parameter values. The 90% confidence intervals of $AUC_t$ and $C_{max}$ were log 0.91~log1.00 and log 1.05~log 1.15, respectively. These values were within the acceptable bioequivalence intervals of log 0.8 to log 1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating that Hepaphil soft capsule is bioequivalent to Nissel tablet.

• 한국임상약학회지
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• 제16권1호
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• pp.52-56
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• 2006

Aceclofenac, a nonsteroidal antiinflammatory agent of a phenylacetic acid type, has been used for rheumatoid arthritis and osteoarthrits. Although the metabolic pathway of aceclofenc is relatively well-known in vitro, pharmacokinetic profiles of its three major or metabolites are still unclear in human. The present study was designed to investigate pharmacokinetic profiles of the metabolites of aceclofenac, and to evaluate the bioequivalence of the generic preparation of aceclofenac 100 mg tablet. Blood samples were serially collected for a period of 12 hours following a single oral administration of 100 mg aceclofenac in 20 healthy human volunteers. A simple protein precipitation with acetonitrile was employed to purify those substances from plasma. Aceclofenac, diclofenac, 4'-hydroxyaceclofenac and 4'-hydroxy-diclofenac in heparinized plasma were simultaneously measured with flufenamic acid, an internal standard, using HPLC coupled to a tandem mass spectrometer. Time courses of 4'-hydroxydiclofenac, diclofenac and aceclofenac plasma concentrations were clearly revealed, and the pharmacokinetic properties were analyzed. The 90% confidence intervals for the ratios of test/reference for log-transformed AUC and $C_{max}$ lie within 0.80-1.25.

• Journal of Pharmaceutical Investigation
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• 제28권4호
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• pp.231-239
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• 1998

A $3{\times}2$ crossover design is considered for the bioequivalence of two test formulations with a control. It could be considered as a better choice over $3{\times}3$ crossover design because of the cost and experimental duration. Oh et al.(1998) derived $3{\times}2$ crossover design and discussed its benefits over the typical crossover designs. We consider here the statistical models for $3{\times}2$ crossover design and show its statistical properties. The statistical procedures for the bioequivalence in $3{\times}2$ crossover design are shown through an example and the results are summarized by satisfying the 3 standards that proposed by the Korea Food and Drug Administration Guidelines for Bioequivalence.

• Journal of Pharmaceutical Investigation
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• 제24권2호
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• pp.67-72
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• 1994

Bioequivalence (BE) test of biphenyl dimethyl dicarboxylate (DDB) tablets was performed. Normal healthy male volunteers (n = 20) were randomly divided into 2 groups, and reference $(Nissel{\circledR})$ and test $(Livital{\circledR})$ tablets of DDB $(25mg{\times}8\;Tab.\;= \;200\;mg)$ were given orally by balanced two-period cross-over design. The serum concentration was determined by high performance liquid chromatography. The pharmacokinetic parameters, AUC, $C_{max}$, and $T_{max}$ obtained after drug administration were statistically analyzed. Statistical evaluation of the data involved an analysis of variance (ANOVA) for cross-over design. The results were within 20% differences of mean value in AUC, $C_{max}$, and $T_{max}$ between reference and test tablets. The results of ANOVA showed no significant differences for "between group or subject" and "period". The test tablet was bioequivalent with the reference tablet in the AUC, $C_{max}$, and $T_{max}$.

• Journal of Pharmaceutical Investigation
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• 제29권4호
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• pp.361-365
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• 1999

The bioequivalence of 'Bearcef tablet' (Daewoong Pharmaceutical Co.), containing 250 mg cefuroxime (as cefuroxime axetil), in reference to 'Zinnat tablet' (GlaxoWellcome Korea Co.) was evaluated in 16 normal volunteers $(age\; 21{\sim}29\;yrs)$ following the oral administration. After one tablet was administered, blood was taken at predetermined time intervals and the concentration of the drug in plasma was quantitated with an HPLC method. AUC, $C_{max}$ and $T_{max}$ were calculated and statistically analyzed for the bioequivalence of the two products. The results showed that the differences in AUC, $C_{max}$ and $T_{max}$ between two products were 6.92%,3.49% and 5.26%, respectively. The powers for AUC, $C_{max}$ and $T_{max}$ were >90%, >90% and 89.0%, respectively. Confiderice intervals for these parameters were all within ${\pm}20%$. Judging based on the above results, 'Bearcef tablet' is regarded to be bioequivalent to 'Zinnat tablet'.

• 약학회지
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• 제33권4호
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• pp.229-236
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• 1989

Even though two different preparations are chemically equivalent, the variance of bioavailability differenciates the clinical effect of preparations, so that the preparations need to be evaluated by comparing bioavailability in vivo as well as chemical equivalence. In this study, bioequivalence tests of commercially available isoniazid tablets A, B, C and D (standard) were performed to give some guidelines to bioequivalence test. The bioavailability parameters obtained by drug administeration were statistically analyzed. Statistical evaluation of the data involved an analysis of variance for a cross over design. Cross over design was employed with 8 healthy volunteers. The results were within 20% difference of mean value in the AUC, Cmax, Tmax and amount of urinary excretion (Au) between standard and isoniazid tablets. The results of ANOVA showed no significant differences for 'group or sequence', but almost not for 'between subjects'. The tablet. A, B and D were within 20 min, but tablet C was within 50 min. Tablet A was biologically equivalent in the Au. tablet B biologically equivalent in the Au and AUC. Tablet C was biologically equivalent in the Au. The relationship between the dissolution rate and Au was significant.

• 약학회지
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• 제44권4호
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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).

• 한국임상약학회지
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• 제19권1호
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• pp.61-64
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• 2009

The study was designed to compare the rate and extent of absorption of two enalapril tablets (10 mg), which has been widely used for the treatment of hypertension. This bioequivalence study was conducted using a standard preparation as reference and a generic as test in 24 male healthy volunteers. After an overnight fast, a single dose of the test or reference drugs were given with a washout period of 7 days. Heparinized blood samples were serially collected up to 10 hr. Plasma enalapril concentrations were quantified using a validated LC-MS/MS method. The data obtained for each subject was evaluated for $C_{max}$ and $AUC_{10hr}$ with respect to 90% confidence interval for log-transformed data. The 90% confidence intervals were log(0.9384)~log(1.1160) for $AUC_{10hr}$ and log(0.9482)~log(1.1474) for $C_{max}$. Thus, we concluded that the test and reference formulation are bioequivalent in terms of rate and extent of absorption.

• Journal of Pharmaceutical Investigation
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• 제27권3호
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• pp.207-212
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• 1997

The bioequivalence of two nabumetone tablets was evaluated in 16 normal male volunteers $(age\;21{\sim}30\;yrs)$ following oral administration. Test product was 'Nacton tablet' made by Jin Yang Pharmaceutical Co. and reference product was 'Unimeton tablet' made by Dong Kwang Pharmaceutical Co.. After one tablet containing 500 mg of nabumetone was administered, blood was taken at predetermined time intervals and the concentration of 6-methoxy-2-naphthylacetic acid, active metabolite of nabumetone, in plasma was determined with an HPLC method using fluorescence detector. AUC, $C_{max}$ and $T_{max}$ were calculated and statistically analyzed for the bioequivalence of the two products. The results showed that the differences in AUC, $C_{max}$ and $T_{max}$ between two products were 3.66%, 6.87% and 1.85%, respectively. The powers$(1-{\beta})$ for AUC, $C_{max}$ and $T_{max}$ were 91.4%, 88.9% and 81.1%, respectively. Detectable differences$({\Delta})$ and confidence intervals were all less than 20%. All of these parameters met the criteria of FDA for bioequivalence, indicating that "Nacton tablet" is bioequivalent to 'Unimeton tablet'.