• YAKHAK HOEJI
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• v.34 no.5
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• pp.334-340
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• 1990

The bioequivalence of Mandol and Mancef (cefamondole nafate injection preparation) was investigated for 8 healthy human volunteers. Cefamandole nafate hydrolysis to cefamandole base in the blood and shows antibacterial activity. As the rate of the hydrolysis can be varied according to the buffer used in the preparation, the bioequivalence of cefamandole nafate I.V. was studied. A new HPLC method, the column switching technique, was developed and used for the simultaneous determination of cefamandole and cefamandole nafate in the plasma and in the urine. There were no statistically significant difference in between Mandol and Mancef for the parameters of AUC and Cp 0.25 hr even through the power of the test was not enough.

• The Korean Journal of Pharmacology
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• v.26 no.2
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• pp.219-226
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• 1990

Enalapril maleate tablets of two different producers were tested for bioequivalence. Enalapril is rapidly metabolized to an active metabolite, enalaprilat which inhibits angiotensin-converting enzyme (ACE). The pharmacokinetics of enalapril maleate and the time course of inhibition of plasma ACE activity after administration of the drugs were studied. Two single doses of 10mg each of enalapril maleate were administered orally to twelve male volunteers in a balanced, randomized, two-way crossover investigation. Plasma enalaprilat concentrations were determined over a 23-hour after the dose by enzyme inhibition assay and enalapril by the same method following in vitro hydrolysis. Urinary recoveries of enalapril and enalaprilat were determined for the calculation of renal clearance. Plasma ACE activity was determined by an enzyme assay. Peak plasma levels of enalapril were observed about 1 hour after the doses, and practically all enalapril had disappeared from plasma within 6 hour. Peak enalapril concentrations of both formulations were almost identical ($Vasotec^{\circledR}$, 61.38 ng/ml; $Beartec^{\circledR}$, 64.27 ng/ml). The values of the pharmacokinetic parameters of enalaprilat computed for $Vasotec^{\circledR}$ and $Beartec^{\circledR}$ tablets are presented in that order; area under the curve=330.63:320.96 $ng{\cdot}hr/ml$; peak concentration=38.63:39.43 ng/ml; time to peak=3.83:4.08 hour; elimination half-life=3.95:3.92 hours. No statistically significant difference was detected when area under the curve and all other parameters were compared. Using criteria of 95% confidence interval for the comparison of these parameters, only the upper limits of area under the curve and time to peak of enalapril were over 120%. All the parameters of enalaprilat were acceptable. Percent inhibition of plasma ACE to plasma enalaprilat concentration showed the sigmoid concentration-inhibition relationship. Time courses of plasma ACE inhibition after the administration of both formulations were quite similar. The formulations were found to be equivalent when compared on the premise that no significant difference was detected when pharmacokientic parameters and inhibition of ACE activity were compared, based on the confidence limits analysis.

• 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 Pharmaceutical Investigation
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• v.28 no.4
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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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• v.24 no.2
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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 $T_{max}$.

• 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.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 $T_{max}$.

• Analytical Science and Technology
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• v.14 no.3
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• pp.221-229
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• 2001

The bioequivalence study of two tiropramide products was evaluated in 16 health male volunteers following intra-muscular injection. Test product was Tiram$^{(R)}$ injection (S Pharm. Co, Ltd.) and reference product was Tiropa$^{(R)}$ injection(D Pharm. Co., Ltd.). The drug concentration in plasma was determined by GC/MS for over a period of 8 hours after injection. Analysis of variance reveal that there are no differences in AUC (area under the plasma concentration-time curve from time zero to infinity), Cmax (maximum plasma concentration) and Tmax (time to reach Cmax). The differences of mean AUC, Cmax and Tmax between two products were 0.73, -1.385 and -12.994%, respectively. Minimum detectable differences (%) at ${\alpha}=0.05$ were all less than 20% given as a guideline (10.05, 17.90 and 19.01% for AUC, Cmax and Tmax, respectively). From these results, the two formulations of tiropramide are bioequivalent and thus, may be prescribed interchangeably.

• The Korean Journal of Applied Statistics
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• v.28 no.3
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• pp.529-540
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• 2015

A cross-over design is frequently used in clinical trials (especially in bioequivalence tests with a parametric method) for the comparison of two treatments. Missing values frequently take place in cross-over designs in the second period. Usually, subjects that have missing values are removed and analyzed. However, it can be unsuitable in clinical trials with a small sample size. In this paper, we compare single imputation methods in a $2{\times}2$ cross-over design when missing values exist in the second period. Additionally, parametric and nonparametric methods are compared after applying single imputation methods. A Monte-Carlo simulation study compares type I error and the power of methods.

• Journal of Pharmaceutical Investigation
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• v.34 no.5
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• pp.379-383
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• 2004

Statistical interpretations in a bioequivalence trial are considered and studied when the missing observations occurred in $2\;{\times}\;2$ crossover experiment. Patel (1985) suggested the approximate test procedures for carryover effect and drug effect in $2\;{\times}\;2$ crossover design when some of data are missing in the second period. A modified Patel method is newly proposed to the bioequivalence trial and it is compared with the current method through the simulation study.