국소 피부용 부신피질 스테로이드제제의 생물학적동등성시험 가이던스 : Topical Dermatologic Corticosteroids In Vivo Bioequivalence

정성희,최선옥,엄소영,정서정,김주일,정수연 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.6

After new medical system of separation of dispensary from medical practice was started in 2000 in Korea, to expand bioequivalence-proven drug products and to ensure the credibility of the therapeutic equivalence of generic drugs are hot issues in Korea. It will be obligatory to submit bioequivalence reports for getting licenses of all generic prescription drugs in the near future. Like other countries such as US and Japan, the KFDA also has a plan to re-evaluate the already approved drugs by bioequivalence studies. Therefore, it becomes more necessary to develop bioequivalence-demonstrating methods for specific preparations such as topical drug products among already approved drug products. There are some differences between US and Japanese guidances of bioequivalence studies of generic drug products for topical use. The information on Japanese guidance and the guidance's Q&As is already provided in our previous paper. In this paper. we examined the US guideline published in 1995 and compared with the Japanese guideline. which will give a useful information to make a guidance on bioequivalence studies of topical drug products in Korea.

국소용 후발의약품의 생물학적동등성시험을 위한 가이드라인

최선옥,정성희,엄소영,정서정,김주일,정수연 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.4

A new medical system of separation of dispensary from medical practice was started in 2000 in Korea. To expand bioequivalence-proven drug products and to ensure the credibility of the therapeutic equivalence of generic drug are hot issues in Korea. The KFDA also has a plan to revise the pharmaceutical affairs law that bioequivalence reports of all the generic prescription drugs should be submitted to the KFDA in the application for drug approval. Therefore, it becomes more necessary to develop bioequivalence-demonstrating methods for specific preparations such as topical drug products. There are some differences between US and Japanese guidances of bioequivalence studies of generic drug products for topical use. In this paper, we examined the recently published Japanese guideline, Guideline for Bioequivalence Studies of Generic Products For Topical Uses, and Q&A of the guideline, which will be references to make a guidance on bioequivalence studies of topical drug products in Korea.

Reverse-phase liquid chromatography with electrospray ionization/mass spectrometry for the quantification of pseudoephedrine in human plasma and application to a bioequivalence study

Kim, JinKi,Jee, JunPil,Park, JeongSook,Kim, Hyung Tae,Kim, ChongKook Georg Thieme Verlag Stuttgart, New York 2011 Arzneimittel Forschung Vol.61 No.5

<P>A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin was used as the internal standard (I.S.). Sample preparation was performed with a deproteinization step using acetonitrile. Pseudoephedrine and I.S. were successfully separated using gradient elution with 0.5% trifluoroacetic acid (TFA) in water and 0.5% TFA in methanol at a flow-rate of 0.2 mL/min. Detection was performed on a single quadrupole mass spectrometer by a selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. The ESI source was set at positive ionization mode. The ion signals of m/z 166.3 and 180.2 were measured for the protonated molecular ions of pseudoephedrine and I.S., respectively. The lower limit of quantification (LLOQ) of pseudoephedrine in human plasma was 10 ng/mL and good linearity was observed in the range of concentrations 10–500 ng/mL (R2 = 1). The intra-day accuracy of the drug containing plasma samples was more than 97.60% with a precision of 3.99–11.82%. The inter-day accuracy was 99.36% or more, with a precision of 7.65–18.42%.By using this analytical method, the bioequivalence study of the pseudoephedrine preparation was performed and evaluated by statistical analysis of the log transformed mean ratios of pharmacokinetic parameters. All the results fulfilled the standard criteria of bioequivalence, being within the 80–125% range which is required by the Korea FDA, US FDA, and EMEA to conclude bioequivalence. Consequently, the developed reverse-phase LC-ESI-MS method was successfully applied to bioequivalence studies of pseudoephedrine in healthy male volunteers.</P>

Bioequivalence of Cholicerin Soft Capsule to Gliatilin Soft Capsule (Choline Alphoscerate 400 mg)

Kang, Hyun-Ah,Kim, Se-Mi,Kang, Seung-Rae,Kang, Min-Sun,Lee, Sang-No,Kwon, In-Ho,Yoo, Hee-Doo,Kim, Yoon-Gyoon,Lee, Yong-Bok The Korean Society of Pharmaceutical Sciences and 2010 Journal of Pharmaceutical Investigation Vol.40 No.2

The purpose of the present study was to evaluate the bioequivalence of two choline alphoscerate soft capsules, Gliatilin soft capsule (Daewoong Pharmaceuticals Co., Ltd.) and Cholicerin soft capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Serum concentrations of choline after oral administration of choline alphoscerate were determined using a validated LC/MS/MS method. This method showed linear response over the concentration range of 0.5-20 ${\mu}g$/mL with correlation coefficient of 0.9999. The lower limit of quantitation using 100 ${\mu}L$ of serum was 0.5 ${\mu}g$/mL which was sensitive enough for pharmacokinetic studies. Thirty six healthy male Korean volunteers received each medicine at the choline alphoscerate dose of 1200 mg in a $2{\times}2$ crossover study. There was a one-week washout period between the doses. Blood samples were taken at predetermined time intervals up to 8 hr. $AUC_t$ (the area under the serum concentration-time curve from time 0 to 8 hr) was calculated by the linear trapezoidal rule method. $C_{max}$ (the maximum serum drug concentration) and $T_{max}$ (the 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 Cholicerin/Gliatilin were log0.9998-log1.1172 and log0.9938-1.0944, respectively. These values were within the acceptable bioequivalence intervals of log0.80-log1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Cholicerin soft capsule and Gliatilin soft capsule are bioequivalent.

Pharmacokinetic and Bioequivalence Study of Zolpidem Tartate in Healthy Volunteers

( Jun Sung Park ),( Ja Hye Myung ),( Hun Sik Wang ),( Ja Seong Koo ),( Wonk Yung Cho ),( Hee Jun Park ),( Min Soo Kim ),( Jeong Soo Kim ),( Kwang Ho Cha ),( Sung Joo Hwang ) 한국약제학회 2011 Journal of Pharmaceutical Investigation Vol.41 No.3

In this study simple and sensitive high performance liquid chromatographic method using a commercially available column, was developed and validated for the determination of zolpidem tartrate in human plasma. The developed method with suitable validation was applied to a bioequivalence study of two different kinds of zolpidem tartrate. Two different formulations containing 10 mg of zolpidem tartate (CAS: 99294-93-6) were compared in 24 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence. The study was performed in an open, single dose randomized, 2-sequence, cross-over design in 24 healthy male volunteers with a one-week washout period. Blood samples for pharmacokinetic profiling were drawn at selected times during 12 h. The mean AUC0-12h, Cmax, Tmax and T1/2 were 676.6±223.4 ng·h·mL-1, 177.4±34.2 ng·mL-1, and 0.8±0.4 and 3.5±2.1, respectively, for the test formulations, and 640.7±186.6 ng·h·mL-1, 193.0±64.5 ng·mL-1, and 0.9±0.4 and 2.7±0.9, respectively, for the reference formulation. Both primary target parameters AUC0-12h and Cmax were log-transformed and tested parametrically by analysis of variance (ANOVA). 90% confidence intervals of AUC0-12h and Cmax were in the range of acceptable limits of bioequivalence (80- 125%). Based on these results, the two formulations of zolpidem tartate are considered to be bioequivalent.

Pharmacokinetic properties and bioequivalence of geftinib 250 mg in healthy Korean male subjects

Seol Ju Moon,Yunjeong Kim,Ji-Young Jeon,Shin-Jung Park,Yong Geun KWAK,김민걸 대한임상약리학회 2021 Translational and Clinical Pharmacology Vol.29 No.3

Gefitinib is an anti-cancer drug used to treat non-small cell lung cancer. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 2 orally administered gefitinib 250 mg tablets in healthy Korean subjects. A randomized, open-label, single-dose, crossover bioequivalence study was conducted. A total of 50 healthy male volunteers were randomized into 2 sequence groups. During each treatment, the subjects received the test or reference formulation of 250 mg gefitinib with a washout period of 21 days. The plasma samples were collected at pre-dose and up to 144 hours post-dose, and plasma drug concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated, and the formulations were considered as bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios were within the bioequivalence limits of 0.8 to 1.25. Forty-one subjects completed the study and were included in the pharmacokinetic analysis. The 90% CIs of the geometric mean ratios of the test formulation to the reference formulation were 0.8115 to 0.9993 for maximum plasma concentration and 0.9119 to 1.0411 for area under the plasma concentration versus time curve from dosing to the last measurable concentration. There were no serious or unexpected adverse events during the study. In healthy Korean adult subjects, the test and reference formulations of gefitinib 250 mg had similar pharmacokinetic parameters and similar plasma concentration-time profiles. The test formulation of gefitinib met the regulatory criteria for assuming bioequivalence. Both formulations were safe and well-tolerated.

기저치를 가진 생물학적 동등성 평가의 통계적 고찰: 내인성 제제 사례연구

박상규 ( Sang-gue Park ),김상영 ( Sangyoung Kim ) 한국보건정보통계학회(구 한국보건통계학회) 2018 한국보건정보통계학회지 Vol.43 No.2

Objectives: To assess bioequivalence between two endogenous drugs in 2 × 2 crossover trial with baseline measurements. Methods: Two statistical methods are applied to assess bioequivalence between two endogenous drugs in 2 × 2 crossover trials. The first method is based on the current regulatory guideline published by Ministry of Food and Drug Safety (MFDS), which is based on the difference between baseline measurements and responses. The second method is more general approach, so-called general linear model method, which is defined the baseline measurements as covariates. Results: The first method based on current guideline shows that two drugs are not bioequivalent; however, the second method by general linear model shows that two drugs are bioequivalent. When the baselines of the subjects are expected to be highly variable, general linear model approach is more suitable to assess the bioequivalence by adjusting high subjects’ variations. Conclusions: General linear model with covariates should be considered in assessing bioequivalence of endogenous substances when highly subject variations of baseline measurements are expected.

Bioequivalence Assessment of Nabumetone Tablets in Healthy Korean Volunteers

Park, Moon-Hee,Shin, In-Chul The Korean Society of Applied Pharmacology 2007 Biomolecules & Therapeutics(구 응용약물학회지) Vol. No.

This study was performed to evaluate the bioequivalency between the Osmetone$^{TM}$ Tablet (Myeongmoon Pharm. Co., Ltd.) as a test formulation and the Relafen$^{TM}$ Tablet (Handok Pharm. Co., Ltd.) as a reference formulation. Twenty-four healthy male volunteers were administered the formulations by the randomized Latin square crossover design, and the plasma samples were determined by a high performance liquid chromatography (HPLC) with Ultra-Violet (UV) detector. AUC$_t$, C$_{max}$ and T$_{max}$ were obtained from the time-plasma concentration curves, and log-transformed AUC$_t$ and C$_{max}$ and log-untransformed T$_{max}$ values for two formulations were compared by statistical tests and analysis of variation. AUC$_t$ was determined to be 897.8${\pm}$431.1 ug.hr/ml for the reference formulation and 902.3${\pm}$408.4 ug.hr/ml for the test formulation. The mean values of C$_{max}$ for the reference and test formulations were 24.2${\pm}$8.9 and 24.0${\pm}$9.5 ug/ml, respectively. The AUC$_t$ and C$_{max}$ ratios of the reference Relafen$^{TM}$ Tablet to the test Osmetone$^{TM}$ Tablet were +5.01% and -0.83%, respectively, showing that the mean differences were satisfied the acceptance criteria within 20%. The results from analysis of variance for logtransformed AUC$_t$ and C$_{max}$ indicated that sequence effects between groups were not exerted and 90% confidence limits of the mean differences for AUC$_t$ and C$_{max}$ were located in ranges from log 0.80 to log 1.25, satisfying the acceptance criteria of the KFDA bioequivalence. The Osmetone$^{TM}$ Tablet as the test formulation was considered to be bioequivalant to the Relafen$^{TM}$ Tablet used as its reference formulation, based on AUC$_t$ and C$_{max}$ values.

Bioequivalence of Boryung Torsemide Tablet to Torem Tablet (Torasemide 10 mg) by High Performance Liquid Chromatography/UV Detector

Cho, Hea-Young,Kang, Hyun-Ah,Park, Chan-Ho,Kim, Se-Mi,Kim, Dong-Ho,Park, Sun-Ae,Kim, Kyung-Ran,Hur, Hyeon,Lee, Yong-Bok The Korean Society of Pharmaceutical Sciences and 2005 Journal of Pharmaceutical Investigation Vol.35 No.5

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.

Bioequivalence Comparison of Two Formulations of Fixed-Dose Combination Glimepiride/Metformin (2/500 mg)Tablets in Healthy Volunteers

Jung, Sang-hoon,Chae, Jung-woo,Song, Byung-jeong,Kwona, Kwang-il Shaheed Beheshti University of Medical Sciences 2014 Iranian journal of pharmaceutical research Vol.13 No.2

<P>Glimepiride/metformin (2/500 mg) is an oral antihyperglycemic agent for the treatment of type 2 diabetes. A generic glimepiride/metformin (2/500 mg) fixed-dose combination (FDC) tablet was developed recently. This study was designed to collect data for submission to Korean regulatory authorities to allow the marketing of the test formulation. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy male adult volunteers. This single-dose, randomized, double-blind, two-way crossover trial was conducted at Bestian Medical Center in Bucheon, Korea. In total, 40 male Korean volunteers were enrolled. The subjects were randomized to receive an FDC tablet containing the glimepiride/metformin (2/500 mg) test or reference formulation, and pharmacokinetic(PK) parameters were measured. After a 1-week washout period, the other formulation was administered and the PK parameters were measured again. The C<SUB>max </SUB>and AUC<SUB>t </SUB>were determined from blood samples obtained at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 h after drug administration. Bioequivalence was considered established if the 90% CIs of the geometric mean ratios(GMRs) of the test-to-reference formulations for C<SUB>max </SUB>and AUC<SUB>t </SUB>were within the predetermined regulatory range of 80-125%. In total, 40 healthy male subjects were enrolled and completed the study (mean [SD] age, 23.2[2.26]years[range, 19-30years];weight, 68.95[8.30]Kg[range, 52.0-87.0 Kg]; and height, 175.4[5.34] cm[range, 164-189 cm]). The GMRs(90% CI) of the glimepiride C<SUB>max </SUB>and AUC<SUB>t </SUB>were 1.006(0.947-1.069) and 1.010(0.953-1.071), respectively. For metformin, the values were 1.019(0.959-1.083) and 1.035(0.989-1.084), respectively. The test and reference formulations had similar PK parameters. The test formulation of glimepiride/metformin (2/500 mg) FDC tablets met the Korean regulatory criteria for bioequivalence. </P>