• Korean Journal of Clinical Pharmacy
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• v.21 no.2
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• pp.145-155
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• 2011

The objective of this study was to determine whether any pretreatment parameters were associated with pharmacological effect or toxicity parameters after vincristine administration and to describe a mathematical model, which explains the interpatient pharmacodynamic variability. The relationship between patient characteristics and vincristine dose and hematological toxicity were evaluated. 68 pediatric and adolescence patients and 107 adults with acute lymphoblastic leukemia were treated with vincristine $1.5mg/m^2/day$ IV and other anticancer drugs as scheduled. Complete blood counts and other blood test results were obtained. The input variables were age, gender, weight, lean body weight (LBW), height, body surface area, vincristine dose and total vincristine dose. The outcome measures were nadir values (white blood cells, absolute neutrophil counts, hemoglobin, and platelets); the absolute decrease, relative decrease, and survival fraction of blood cells. Polynomial regression analysis was carried out to determine the other significant covariates. The variability of $WBC_{nadir}$ was modeled with good precision and accuracy with a two-covariate model. This model should be validated and improved on with further clinical data. We believe that such pharmacodynamic modeling should be explored further to determine its performance and clinical relevance compared with modeling using pharmacokinetic parameter.

• Journal of Pharmaceutical Investigation
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• v.34 no.1
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• pp.43-48
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• 2004

The purpose of the present study was to evaluate the bioequivalence of two nizatidine capsules, Axid (Lilly Korea Pharm. Co., Ltd.) and Nex (Bi-nex Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The nizatidine release from the two nizatidine capsules in vitro was tested using KP Apparatus method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solutions and water). The dissolution prefers of two nizatidine capsules were very similar at all dissolution media. Twenty four normal male volunteers were divided into two groups with a randomized 22 crossover study. After two capsules (300 mg nizatidine) were orally administrated, blood was taken and the concentrations of nizatidine in serum were determined using HPLC with UV detector. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were determined. The result showed that the differences in $AUC_t$, $C_{max}$ and $T_{max}$ between two nizatidine capsules based on the Axid were -6.16%, -8.26% and -1.82%, respectively. There were no sequence effects between two capsules in these parameter. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(125)(e.g., $log(0.91){\sim}log(0.97)$ and $log(0.85) {\sim}log(0.99)$ for $AUC_t$ and $C_{max}$ respectively), indicting that Nex capsule is bioequivalent to Axid capsule.

• Korean Journal of Clinical Pharmacy
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• v.26 no.4
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• pp.312-317
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• 2016

Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.

• Korean Journal of Clinical Pharmacy
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• v.16 no.1
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• pp.34-39
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• 2006

Fexofenadine, one of selective histamine $H_1$ receptor antagonists, has been used for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. The bioequivalence of two fexofenadine hydrochloride preparations, containing 120 mg fexofenadine hydrochloride, was evaluated according to the guidelines of Korea Food & Drug Administration(KFDA). The test product was Hanmi Fexofenadine Hydrochloride Tablet $120mg^{(R)}$ made by Hanmi Pharm. Co. and the reference product was Allegra Tablet $120mg^{(R)}$ made by Handok Parmaceuticals Co.. Twenty healthy male subjects were randomly divided into two groups and a $2{\times}2$ cross-over study was employed. After one tablet was orally administered, blood was taken at predetermined time intervals and the concentration of fexofenadine in plasma was determined using a validated HPLC method with fluorescence 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 $0.844{\sim}log$ 1.149 and log $0.833{\sim}log$ 1.109, 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 Hanmi Fexofenadine Hydrochloride Tablet 120 mg is bioequivalent to Allegra Tablet 120 mg.

• Journal of Pharmaceutical Investigation
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• v.36 no.1
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• pp.53-58
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• 2006

Fexofenadine, one of selective histamine $H_1$ receptor antagonists, has been used for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria. The bioequivalence of two fexofenadine hydrochloride preparations, containing 180 mg fexofenadine hydrochloride, was evaluated according to the guidelines of Korea Food & Drug Administration (KFDA). The test product was Hanmi Fexofenadine Hydrochloride $Tablet^{\circledR}$ made by Hanmi Pharm. Co. and the reference product was Allegra $Tablet^{\circledR}$ made by Handok Parmaceuticals Co.. Twenty healthy male subjects were randomly divided into two groups and a $2\;{\time}\;2$ cross-over study was employed. After one tablet was orally administered, blood was taken at predetermined time intervals and the concentration of fexofenadine in plasma was determined using a validated HPLC method with fluorescence 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 $log\;0.822{\sim}log \;1.142$ and $log\;0.848{\sim}log\;1.172$, 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 Hanmi Fexofenadine Hydrochloride Tablet is bioequivalent to Allegra Tablet.

• YAKHAK HOEJI
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• v.45 no.6
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• pp.650-655
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• 2001

Carvedilol is a nonselective $\beta$-blocking agent with vasodilating properties that are attributed mainly to its blocking activity at $\alpha$$^{1}$-receptors. Carvedilol is used in the treatment of mild to moderate hypertention and angina pectoris and is often used in combination with other drugs. This study was carried out to evaluate the bioequivalence and pharmacokinetics of two carvedilol 25mg tablet formulations according to the guidelines of Korea Food and Drug Administration (KFDA). Twenty healthy volunteers are enrolled and received a single dose (25mg as carvedilol) of each drug in the fasting state, in a randomized 2-way crossover design. After oral administration, blond samples were collected for a period of 30 hours. Plasma concentrations of carvedilol were determined by a rapid and sensitive HPLC method with spectrofluorometric detection. The major pharmacokinetic parameters such as AU $C_{0-}$30hr/, AU $C_{inf}$ , $C_{max}$, $T_{max}$, $t_{1}$2 / Cl/F and V $_{\beta}$//F were calculated. ANOVA test and t-test were utilized for the statistical analysis of each parameter. The results showed that the differences in AU $C_{0-}$30hr/, $C_{max}$ and $T_{max}$ between two were ~5.66, 1.74 and 0.00%, respectively. Minimum detectable differences ($\Delta$) at $\alpha$=0.05 were less than$\pm$ 20% except $T_{max}$ (8.44, 18.36, and 33.86%, respectively). The 90% confidence intervals of all parameters were within $\pm$20% (-10.60~ -0.72, -9.00~12.49 and -19.81~19.81%, respectively). Therefore, it is concluded that the two formulations are bioequivalent for both the extent and the rate of absorption after single dose administration.ation.ion.ion.ation.ion.n.

• Journal of Pharmaceutical Investigation
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• v.34 no.6
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• pp.499-504
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• 2004

Paroxetine, a potent and selective serotonine reuptake inhibitor, has been used for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. The bioequivalence of two paroxetine preparations was evaluated according to the guidelines of Korea Food & Drug Administration (KFDA). The test product was Samchully Paroxetine $tablet^{\circledR}$ made by Samchully Pharm. Co. and the reference product was Seroxat $tablet^{\circledR}$ made by GlaxoSmithKline. Twenty healthy male subjects, $22.4{\pm}2.6$ years old and $63.8{\pm}4.2\;kg$, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 20 mg paroxetine was orally administered, blood was taken at predetermined time intervals and the concentration of paroxetine in plasma was determined using a validated HPLC method with fluorescence detector. Two pharmacokinetic parameters, $AUC_t$ and $C_{max}$, were calculated and analyzed statistically for the evaluation of bioequivalence of 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 0.84-log 1.16 and log 0.85-log 1.14, 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 Samchully Paroxetine tablet is bioequivalent to Seroxat tablet.

• Translational and Clinical Pharmacology
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• v.26 no.4
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• pp.166-171
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• 2018

Although there are many commercially available training software programs for pharmacokinetics, they lack flexibility and convenience. In this study, we develop simulation software to facilitate pharmacokinetics education. General formulas for time courses of drug concentrations after single and multiple dosing were used to build source code that allows users to simulate situations tailored to their learning objectives. A mathematical relationship for a 1-compartment model was implemented in the form of differential equations. The concept of population pharmacokinetics was also taken into consideration for further applications. The source code was written using R. For the convenience of users, two types of software were developed: a web-based simulator and a standalone-type application. The application was built in the JAVA language. We used the JAVA/R Interface library and the 'eval()' method from JAVA for the R/JAVA interface. The final product has an input window that includes fields for parameter values, dosing regimen, and population pharmacokinetics options. When a simulation is performed, the resulting drug concentration time course is shown in the output window. The simulation results are obtained within 1 minute even if the population pharmacokinetics option is selected and many parameters are considered, and the user can therefore quickly learn a variety of situations. Such software is an excellent candidate for development as an open tool intended for wide use in Korea. Pharmacokinetics experts will be able to use this tool to teach various audiences, including undergraduates.

• Journal of fish pathology
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• v.31 no.1
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• pp.23-34
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• 2018

The pharmacokinetic properties of cefadroxil (CDX) were studied after oral administration for 7 days to cultured olive flounders (average 660 g), Paralichthys olivaceus. For examination of pharmaco-kinetic profiles, CDX of 45 to 225 mg/kg body weight was administered at two different water temperatures, $13{\pm}3^{\circ}C$ or $22{\pm}3^{\circ}C$. CDX concentrations were determined in muscle, plasma, gastrointestinal tract, hematopoietic organs and liver by HPLC-MS/MS. Muscle samples were taken at 0.25, 0.5, 1, 3, 7, 14 and 28 days post dose, whereas plasma, gastrointestinal tract, hematopoietic organs and liver concentrations were measured at 1, 3, 7, 14 and 28 days post-dosing. The kinetic profiles of $C_{max}$, $T_{max}$, $T_{1/2}$ of CDX were analyzed by fitting to a non-compartmental model with PKSolver program. The following pharmacokinetic parameters were obtained with oral administration of 45 and 225 mg/kg at 13 and $22^{\circ}C$ in muscle, plasma, gastrointestinal tract, hematopoietic organs and liver, respectively: $C_{max}$ (maximum tissue concentration)=$985.98-5,032.86{\mu}g/kg$, $5,670.99-38,922.23{\mu}g/l$, $2,457.27-10,192.78{\mu}g/kg$, $886.04-3,070.87{\mu}g/kg$ and $1,188.15-3,814.33{\mu}g/kg$; $T_{max}$ (time for maximum concentration)= every 1 day; $MRT_{0-{\infty}}$ (mean residence time)= 1.51-4.74, 2.12-3.06, 4.25-13.18, 1.37-18.66 and 1.78-29.76 days; $T_{1/2}$ (half-life)= 1.08-3.47, 1.14-5.42, 3.56-10.99, 1.17-14.93 and 1.25-28.55 days.

• Korean Journal of Food Science and Technology
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• v.29 no.1
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• pp.167-172
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• 1997

Effect of combined preparation (DWP715) containing Alaska pollack extract, maltol, ascorbic acid and nicotinamide on decreasing of blood alcohol was evaluated in human blood. Treatment of DWP715 prior to administration of 25% alcohol (100 mL) decreased alcohol concentration in blood and showed significant difference after 2 hours. The pharmacokinetic parameters such as area under the concentration-time curve (AUC), $C_{max},\;T_{max}\;and\;T_{1/2}$ were also decreased and delayed when compared with control values. Effects of DWP715 on anti-fatigue and anti-oxidation activities were also studied in the restraint stress model using various parameters (GOT, GPT, LDH values and organ weights) on mild condition and examined through the content of lipid peroxide induced by 2% $CCl_4$ in mouse livers. While GPT level, thymus and adrenal weight were not influenced by DWP715 dosing, LDH, GOT level and spleen weight used as a parameter against fatigue and stress states were recovered almost to the nomal level. Furthermore, lipid peroxidation due to $CCl_4$ was significantly inhibited by DWP715 treatment. These results suggest that DWP715 seems to metabolize the blood alcohol rapidly and to restore the damaged liver and fatigue conditions which was caused by alcohol metabolism to normal condition.