• 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In 2001 US FDA proposed a draft guidance for future in vivo bioequivalence studies.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.

• The Korean Journal of Applied Statistics
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• v.23 no.1
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• pp.139-150
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• 2010

In recent years, more generic drug products became available. The current regulation for assessing the bioequivalence of two drug formulations is based on the concept of average bioequivalence. This approach has been indicated to be insufficient for assessing switchability between two drug formulations and US FDA has adopted individual bioequivalence as one of the bioequivalence criterion since 2001. The US FDA recommends that individual bioequivalence be assessed based on $2\;{\times}\;4$ crossover design, while a $2\;{\times}\;3$ crossover design may be used as an alternative design to reduce the length and cost of the study. In this paper, a statistical procedure for assessment of individual bioequivalence under $3\;{\times}\;2$ crossover designs is proposed and some statistical points are discussed with $2\;{\times}\;3$ crossover design and $2\;{\times}\;3$ extra-reference design through simulation studies.

• The Korean Journal of Applied Statistics
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• v.18 no.1
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• pp.159-171
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• 2005

The US Food and Drug Administration(FDA) recommends that population bioequivalence and individual bioequivalence would be assessed to address the prescribability and switchability between a brand-name drug and its new formulation or generic copy in its 2001 guidance document. The test for population bioequivalence in the latest FDA guidance is recommended in 2 x 4 crossover design, but it turns out to be very conservative. Recently Lee, Shao & Chow(2002), Chow, Shao & Wang(2003) and McNally, Iyer & Mathew(2002) proposed new statistical methods for assessing population bioequivalence between drugs to correct the biasness of current FDA method. Since 2 x 2 crossover experiment is most welcomed design in bioequivalence testing, we adopt their methods to 2 x 2 crossover designs and compare their methodologies with FDA one through the simulation study.

• 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.

• Journal of the Korean Statistical Society
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• v.35 no.3
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• pp.239-250
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• 2006

A $2{\times}2$ crossover design including carryover effect is considered for assessment of population bioequivalence of two drug formulations in a Bayesian framework. In classical analysis, it is complex to deal with the carryover effect since the estimate of the drug effect is biased in the presence of a carryover effect. The proposed method in this article uses uninformative priors and vague proper priors for objectiveness of priors and the posterior probability distribution of the parameters of interest is derived with given priors. The posterior probabilities of the hypotheses for assessing population bioequivalence are evaluated based on a Markov chain Monte Carlo simulation method. An example with real data set is given for illustration.

• 대한임상약리학회:학술대회논문집
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• 1999.12a
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• pp.26-26
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• 1999

• 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.39 no.4
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• pp.233-242
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• 2009

Bioequivalence (BE) studies provide important information in the overall set of data that ensure the availability of safe and effective medicines to patients and practitioners. Thus its determination of proper criterion for assessing BE is very important. BE is frequently expressed or measured by estimating area under the plasma concentration-time curve (AUC) and maximum concentration ($C_{max}$) that are reflective of systemic exposure. In all countries except Canada, the acceptance criteria of BE is that the 90% confidence interval of difference in the average values of logarithmic AUC and $C_{max}$ between test and reference products is within the acceptable range of log(0.8) ${\sim}$ log(1.25). In Canada, unlike other countries, point estimation instead of applying 90% confidence interval is applied to assess $C_{max}$ which is, in essence, more variable than AUC. We also compared other parts of BE guidelines which include a fed study, average BE (ABE), scaled-ABE, population BE (PBE), individual BE (IBE), dropout & withdrawal, sampling frequency & time and number of subjects. This article reviews the most recent BE guidelines of Korea, USA, Europe, Canada and Japan, highlighting the differences focused on Korean BE guidelines compared to other countries. It will help us to revise BE guideline of Korea reflecting international trends. Finally, it is strongly recommended that the extended acceptance criterion for the highly variable drug among all the considering aspects for the revision of current BE guideline has to be adopted into Korea BE guideline in the nearest future.

• Korean Journal of Clinical Pharmacy
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• v.6 no.2
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• pp.19-23
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• 1996

Carbamazepine is an anticonvulsant drug that has been shown to be as effective as phenytoin or phenobarbital in treatment of grand mal and complex partial seizures and is also approved as the drug of choice for treatment of the pain associated with trigerminal neuralgia. And the therapeutic or toxic effects of carbamazepine are better related to plasma concentration than to dosage, which can be attributed to interindividual variability in the pharmacokinetics. A slow rate of carbamazepine dissolution in the gastrointestinal tract is believed to be the cause of its relatively slow and erratic rate of absorption. For these reasons pharmacokinetic evaluation of newly formulated carbamazepine is neccessary. In this study, the bioequivalence in carbamazepine between the $TegretoI^{TM}$ CR tablet (Geigy Co.) and $Carmazepine^{TM}$ CR tablet (Myung In Co.) was evaluated. 12 normal volunteers (age $21\~27$ years old) was divided into two groups, and a randomized cross-over study was employed. The pharmacokinetic parameters ($C_{max},\;T_{max}$ and AUC) obtained of oral administration of each formulatim of carbamazepine 400 mg were evaluated and ANOVA was utilized for the statistical analysis of parameters. $C_{max}\;is\;8.26{\pm}3.1{\mu}g/ml\;(C.V.\;37.3\%)\;in\;TegretoI^{TM}\;and\;9.39\{pm}2.9{\mu}g/ml\;(C.V.\;30.5\%)$ in $Carmazepine^{TM},\;T_{max}\;is\;28.0{\pm}5.9\;hrs(C.V.\;21.1\%)$ in $Tegretol^{TM}\;and\;24.0{\pm}7.2\;hrs(C.V.\;30.2\%)$ in $Carmazepine^{TM}$ and AUC is $786.4{\pm}360.5{\mu}g{\cdot}hr/ml\;(C.V.\;45.8\%)$ in $TegretoI^{TM}\;and\;792.8{\pm}228.6{\mu}g{\cdot}hr/ml\;(C.V.\;28.8\%)$ in $Carmazepine^{TM}$, respectively. As the result of the data, two formulations are bioequvalent, and the lower C.V. of $Carmazepine^{TM}$ in every individual can be merit.

• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.107-112
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• 1998

Lovastatin is a lipid lowering agent for the treatment of hypercholesterolemia and belongs to a new class of pharmacologic compounds called the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors. By competitively inhibiting HMG CoA reductase, lovastatin disrupts the biosynthesis of cholesterol in hepatic and peripheral cells and increases the synthesis of high-density-lipoprotein HDL) receptors. Following oral administration, the lactone ring of lovastatin is hydrolysed to the active inhibitor of HMG CoA reductase, lovastatin acid. Lovastatin is known to have poor oral absorption and wide individual variation. In this study, bioequivalence test of two lovastatin formulations, the test drug ($Lovaload^{TM}$, Chong Kun Dang Pharmaceutical Co.) and the reference drug ($Mevacor^{TM}$, Chung Wae Pharmaceutical Co.) were conducted according to the guidelines of Korea Food and Drug Administration (KFDA). A total of 18 healthy male volunteers, $31.90\pm3.60$ years old and $72.17\;7.88$ kg of body weight in average, were evaluated in a randomized crossover manner with a 2-week washout period. Concentrations of lovastatin acid in plasma were measured upto 12 hours following a single oral administration of eight tablets (20 mg of lovastatin per tablet) by high-performance liquid chromatography with UV detection at 238 nm. The area under the concentration-vs-time curve from 0 to 12 hours $(AUC_{0-12h})$ was calculated by the trapezoidal summation method. The statistical analysis showed that there are no significant differences in $AUC_{0-12h),\;C_{max}\;and\;T_{max}$ between the two formulations ($6.72\%,\;1.52\%,\;and\;0.88\$, respectively). The least significant differences between the formulations at $\alpha$=0.05 were less than $20\%\;(11.65\%,\;19.73\%,\;and\;14.81\%\;for\;AUC_{0-12h},\;C_{max}\;and\;T_{max}$, respectively). The $90\%$ confidence intervals for these parameters were also within $\pm20\%\;(-1.50{\leq}{\delta}{\leq}15.00$, $-12.50{\leq}{\delta}{\leq}15.50,\;and\;-9.64{\leq}{\delta]{\leq}11.40{\leq}\;for\;\;AUC_{0-12h}$ ,$C_{max}\;and\;T_{max}$, respectively). In conclusion, the new generic product $Lovaload^{TM}$ was proven to be bioequivalent with the reference drug.