Since Jul $1^{st}$ 2000, generic substitution has been allowed in Korea with the beginning of 'separation of drug dispensing from prescription'. The management and regulation of generic drugs in order to assure the therapeutic equivalence to the brand-name drug is very important in terms of patient safety. In the United States, there is a hierarchy of regulations and many guidances for this purpose. The 'Federal Drug, Food and Cosmetic Act' and 'Food and Drug Administration Modernization Act(1997)' is in the highest position on the regulation of drugs. Sections 21CFR314 and 21CFR320 of 'Code of Federal Regulation Title 21 Food and Drugs' are quite concrete regarding 'New Drug Application/Abbreviated New Drug Application' and 'Bioequivalence'. The guidelines and guidances issued by the FDA CDER are the easiest to understand. Each state has its own regulations for generic substitution and the US FDA has standard operating procedures (SOP), called 'Manual of Policies and Procedures (MAPP)' for the management of drugs. The US FDA requires that a generic drug have the same standard quality as the brand-name drug. Generic drugs should meet the 'Good Manufacturing Practice' standards and show therapeutic equivalence to the 'reference listed drug (brand-name drug)'. A bioequivalence study should be conducted like an ordinary clinical trial, after the approval of IRB. FDA also inspects the bioequivalence study site and manufacturing facilities. After the approval, the applicant of generic drug should report on qualtity and safety periodically. If this were unmet, FDA would cancel the approval. Therapeutic equivalence is usually proven by bioequivalence, with some exceptions. FDA has clear and strict guidances for the exemption of in vivo bioequivalence study. FDA is trying to be both concrete and flexible for many kinds of drug action modes.

Background : Silymarin formulations show low bioavailability due to its poor solubility. Therefore, developing a formulation which could improve bioavailability was a major issue. In Korea, there are many kinds of silymarin-containing formulations, including Legalon cap. $140^{\circledR}$. We compared the pharmacokinetic characteristics of a generic silymarin formulation developed by H company with those of Legalon cap. $140^{\circledR}$. and speculated on the clinical implications. Methods : The study was conducted as a open-labeled, randomized, 2-way crossover Latin square design in 16 healthy subjects. Subjects were separated into two groups, A and B. Subjects in group A were administered a generic formulation orally, and 1 week later they were administered Legalon cap. $140^{\circledR}$. Subjects in group B were administered the drugs in opposite sequence in the same manner. Dosage administered was 60 mg as silibinin. Serial blood samples were collected till 24 hours after the drug administration. Plasma concentrations of silibinin diastereomers were assayed by HPLC and total silibinin concentrations were obtained. Pharmacokinetic parameters of the two formulations were analyzed by noncompartmental methods. We tested the sequence effect, period effect and differences of parameters between the two formulations by ANOVA. The pharmacokinetic characteristics of two test formulations were compared by 90% confidence intervals for ratios of $AUC_{0-\infty}$ and $C_{max}$, and the other kinetic parameters by student t-test. Results : Mean $AUC_{0-\infty}$ and $C_{max}$ of the generic formulation were 1.46 and 3.06 times higher than those of Legalon cap. $140^{\circledR}$, respectively $(AUC_{0-\infty}\;:\;3766{\pm}1475\;vs.\;2580{\pm}863\;ng{\cdot}hr/mL,\;C_{max}\;:\;1639{\pm}499\;vs.\;535{\pm}181\;ng/mL\;;\;generic\;vs.\;Legalon\;cap.\;140^{\circledR},\;mean\;{\pm}\;SD)$. The differences of $AUC_{0-\infty}$ and $C_{max}$ were statistically significant (p<0.001). $t_{max}$, MRT, and terminal half-life of the two drugs were also statistically different $(t_{max}\;:\;0.73{\pm}0.22\;vs\;1.67{\pm}0.98\;hr,\;MRT\;:\;5.38{\pm}1.65\;vs\;6.11{\pm}1.41\;hr,\;t_{1/2}\;:\;5.48{\pm}1.71\;vs.\;4.47{\pm}1.75\;hr,\;a\;generic\;vs.\;Legalon\;cap.\;140^{\circledR})$. The mean of individual relative bioavailability $(generic/Legalon\;Cap.\;140^{\circledR})$ was 1.46, and the 90% confidence interval was 1.31-1.62. The mean ratio of $C_{max}$ $(generic/Legalon\;Cap.\;140^{\circledR})$ was 3.1, and the 90% confidence interval was 2.47-3.82. Conclusion : The $AUC_{0-\infty}$ and $C_{max}$ of the new generic drug were significantly greater then those of Legalon cap. $140^{\circledR}$. The generic drug was rapidly absorbed, and the increase in oral bioavailability was primarily due to the increase in the early phase absorption. The two formulations were not bioequivalent, and the therapeutic equivalence needs to be evaluated. The clinical implications of greater $AUC_{0-\infty}$ and $C_{max}$ should be investigated by additional clinical studies. The dosage of the generic has not been established by clinical studies, in contrast to that of Legalon Cap. $140^{\circledR}$.

Background : This study was carried out for conducting the drug utilization review of oral benzodiazepines for geriatric patients that are frequently prescribed in geriatric practice and associated with many serious side effects in elderly people. Method : The subjects of this study were the 'Korean Elderly Pharmacoepidemiology Cohort', who were the beneficiaries of Korea Medical Insurance Corporation in 1993 and 1994, over 65 years of age, lived in Pusan metropolitan city. The information about prescribed for benzodiazepines was constructed from the medical claims data, and they included personal identification age, sex, the name of drug, dosage, the date of prescription and the medical institution where the patient admitted. Result : The total number of cases prescribed for benzodiazepines from 1993 to 1994 were 1,518. 988 cases were for female and 530 cases were for male. The most frequently prescribed benzodiazepine was diazepam (59.1 %) and the total prescription proportion of long acting benzodiazepines was 70.8%. The doses of benzodiazepines were almost optimal exept alprazolam which was overdosed somewhat according to geriatric prescription guideline. There was decreasing tendency of diazepam prescription and increasing tendency of lorazepam for 2 years. Conclusion : The use of benzodiazepins with a long duration of action in elderly people are associated with an increased risk of falling and fracture that leads to the decrease of quality of life. So, long half-life benzodiazepines should be prescribed more cautiously in geriatric practice.

Background : Captopril, the first orally active inhibitor of the angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. A model for 24-hour blood pressure considering diurnal variation was expected to be an approach for better understanding of plasma concentration -plasma angiotensin converting enzyme (ACE) activity- hypotensive effect relationships. Methods : Data were obtained from a randomized, single blind, and crossover study in healthy subjects. As a first modeling step, a model for 24-hour ambulatory blood pressure measurement(ABPM) was developed from 12 subjects receiving placebo, then this placebo model was used in a final PK/PD model from 12 subjects receiving captopril 50 mg. A nonlinear mixed-effects model incorporating time gap(hysteresis) between PK and PD steps was applied. Model building was evaluated using the goodness-of-fit criteria and the change in MOFV(minimum objective function value). Results : The time course of drug concentrations was best explained with a first order absorption and elimination one compartment open linear model. The ABPM data was best discribed by a model, which consisted of 2 cosine functions for diurnal fluctuation and a Hill's model using effect compartment for drug effect. Plasma captopril concentrations, plasma ACE activities, and diastolic blood pressures(DBP) were fitted simultaneously $(R^2=0.9357,\;0.9685,\;and\;0.5966,\;respectively)$. The estimated population mean value of clearance(CL/F) and the mean volume of distribution(Vd/F) were 54.2 L/hr(8.6 SE %) and 38.5 L(9.1 SE %), respectively. The plasma ACE activity at steady $state(ACE_{ss})$ and mean DBP were 37.0 U/L(7.6 SE %) and 69.3 mmHg(2.3 SE %), respectively. The maximum predicted fall in DBP was 13.5%(17.5 SE %) from the baseline. Inhibition of ACE activity resulting in 50% maximum hypotensive $effect(ACEI_{50})$ was 48.2% (7.8 SE %). Conclusion : The time course of BP changes in each individual subject could be well characterized by this model. This population pharmacokinetic-pharmacodynamic modeling of captopril can be used in determining the optimal regimen or evaluation of new drugs.

Background : Recently some clinical studies suggest that the stage of the progression in chronic liver disease would be important for colchicine treatment and colchicine may prevent the progression of chronic liver disease, especially, severe chronic active hepatitis(CAH) and early cirrhotic patients. However, in all patient of chronic liver disease, it is very difficult to perform liver biopsy. To decide the stage of colchicine treatment and maximize the pharmacologic effect of colchicine in chronic liver disease, we evaluate the correlation of the effect of colchicine and the shunt index(SI) of TI-201 liver scan instead of liver biopsy. Method : We retrospectively analyzed the first and last laboratory test variables, including albumin, bilirubin, ALT, AST, cholesterol, prothrombin time, and SI, obtained from 131 patients ; 32 moderate CAH, 35 severe CAH, 64 LC (Child A), which were proven with percutaneou liver biopsy. All patients were followed up for more than 2 years and performed TI-201 liver scan and taked colchicine. After we obtained the mean shunt index in three groups and the based shunt index by means of ROC analysis, all patients were divided into two groups on the basis of each shunt indices. The two groups were compared with a change of X value ; the sum of the last X value minus the first X value. [$Z=3.3431-0.8160\;{\times}\;ALT/AST-0.0343\;{\times}\;PT+2.6963\;{\times}\;SI,\; X=e^z/(e^z+ 1)$, as the X value increases from 0 to 1, chronic active hepatitis will progress into liver cirrhosis] Results : Each shunt indices are $0.17\;{\pm}\;0.08$ in moderate CAH, $0.24\;{\pm}\;0.02$ in severe CAH, $0.45\;{\pm}\;0.04$ in LC. On the basis of 0.17, there was no statistical difference of a change of X value between $SI{\geq}0.17$ and SI<0.17 (p=0.09). On the other hand, on the basis of 0.24 and 0.45, there was statistical difference of a change of X value between two groups [$SI{\geq}0.24$ and<0.24 (p=0.011), $SI{\geq}0.45$ and<0.45 (p=0.001)]. We could notice an improvement in $SI{\geq}0.24$ and$SI{\geq}0.45$. Also on the basis of 0.19 which is a cut-point to divide the patients into two groups (moderate CAH vs severe CAH+LC), there was statistical difference of a change of X value between two groups [$SI{\geq}0.19$ and < 0.19 (p=0.012)]. Conclusion : On $SI{\geq}0.19$, colchicine has the effect to prevent progression of chronic liver disease. This results suggest that the SI of TI-201 liver scan may be useful for the evaluation of adequate time of colchicine treatment and prediction of the pharmacologic effect of colchicine.

Background : Terazosin is an ${\alpha}-adrenergic$ receptor blocker and is used for the treatment of mild to moderate hypertension and benign prostatic hyperplasia. Terazosin can be administered once daily because of its high oral bioavailability of about 90% and long half-life of 9 to 12 hours. $TZC^{\circledR}tablet$ is an oral terazosin formulation that was intended to be developed as a generic formulation of $Hytrin^{\circledR}tablet$, an existing oral terazosin formulation in Korea. Therefore, we compared the pharmacokinetic characteristics and tested the bioequivalence of the two formulations in healthy Korean male subjects. Methods: The study was conducted as an open-labeled, randomized, 2-way crossover Latin square design in 18 healthy subjects. Subjects were separated into two groups. Subjects in one group were planned to be administered single doses of $Hytrin^{\circledR}tablets$ orally and one week later single doses of $TZC^{\circledR}tablets$. Subjects in another group were planned to be administered in opposite sequence in the same manner. Originally drugs in each period were to be administered in two divided days to 9 subjects each day, to guarantee the safety and well-being of subjects. But, actually, subjects were administered in three divided days to 7, 7 and 4 subjects respectively, due to private reasons of some subjects. Dosage administered was 1 mg as terazosin. Serial blood samples were collected till 48 hours after the drug administration. Plasma terazosin concentration were assayed by reversed phase HPLC using prazosin as internal standard. Pharmacokinetic parameters of the two formulations were analyzed by noncompartmental methods. We tested the sequence effect, period effect and differences of parameters between the two formulations by ANOVA. The pharmacokinetic characteristics of the two parameters were compared by 90% confidence intervals for ratios of $AUC_{0-{\infty}}$ and Cmax and the other pharmacokinetic parameters by student t-tests. Result : There was no difference in date groups when we analyzed the effect of dispersion of dates of drug administration to subjects using ANOVA, for p value was 0.1209. There were no differences between sequence, period and treatment groups, too. Total AUC of $TZC^{\circledR}tablets$ was $278.74{\pm}79.28\;ng\;{\times}\;hr/ml\;(mean{\pm}SD)$, and that of Hytrin tablet was $276.57{\pm}83.79$. $C_{max}$ of $TZC^{\circledR}tablets$ was $26.61{\pm}7.16\;ng/ml\;(mean{\pm}SD)$, and that of $Hytrin^{\circledR}tablet$ was $26.54{\pm}8.46$. AUC ratio between two formulations in individual subjects was $1.019{\pm}0.138.\;t_{1/2}(terminal\;half-life)$, $T_{max}$(time to maximum concentration), MRT(mean residence time) were similar between two formulations. The 90% confidence interval of total AUC difference between two $formulations(-17.86{\sim}22.20)$ was within the 20% of AUC of $Hytrin^{\circledR}tablet$, a $reference(-55.31{\sim}+51.31)$. The 90% confidence interval of $C_{max}$ difference between two $formulations(-2.44{\sim}2.66)$ was also within the 20% of $C_{max}$ of $Hytrin^{\circledR}tablet(-5.31{\sim}+5.31)$. Therefore, $TZC^{\circledR}tablets$ and $Hytrin^{\circledR}tablet$ were bioequivalent. Conclusion : Bioequivalence study is a clinical trial with human beings as subjects. Therefore, we should conduct clinical trial with due regard to the safety and well-being of subjects. The dispersion of administration dates is likely to occur in actual clinical trial field. There were no statistically significant differences in date groups when analyzed by ANOVA test, and we could conclude that the administration of drugs in three divided days had no effect on the bioequivalence test results of the two formulations. In crossover test, the dispersion of administration dates does not matter because the crossover design structure itself exclude the intersubject variability. Also, the dispersion of administration dates would increase the possibility of concluding that two formulations are not bioequivalent although actually bioequivalent but it is not possible to conclude that two bioequivalent formulations are not bioequivalent. In this study, we concluded that $Hytrin^{\circledR}tablet$ and $TZC^{\circledR}tablets$ are bioequivalent although the dates of administration were dispersed to three days, for the dispersion of dates proved not to affect the bioequivalence test result of two formulations.

Background: Stereotactic pallidotomy is currently used for the symptomatic treatment of patients with advanced Parkinson's disease and motor complications related to drug treatment. However, these procedures are being performed in the absence of follow-up data on their retained effect and levodopa response after the surgery. The purpose of this study was to investigate the levodopa response after unilateral pallidotomy in advanced Parkinson's disease. Method : Clinical evaluation of levodopa responses were measured at baseline, 3, 6, 9, 12 months, and 2, 3, 4 years after surgery by means of the total levodopa equivalents. A set of rating scales(Hoehn and Yahr, Unified Parkinson's Disease Rating Scale, and Schwab and England) was also applied. Fifty patients who had had unilateral pallidotomy for advanced Parkinson's disease were investigated retrospectively. Results: The patient group consisted of 23 men and 27 women with a mean age of $58.6{\pm}11.3$ years. Mean disease duration was $7.22{\pm}4.28$ years. 29 pallidotomies were carried out on the left-and 21 on the right-brain hemisphere. Mean Hoehn and Yahr stage was $2.99{\pm}1.29$ while 'off' and $2.84{\pm}1.19$ while 'on' condition. Mean UPDRS score was $44.29{\pm}26.29$ while 'on' and $67.72{\pm}25.43$ while 'off' condition. The average total levodopa equivalent was 728.86 mg/day before the surgery, 611.12 mg/day after the surgery, and 694.7 mg/day at the last follow-up. After unilateral pallidotomy, there was no need to increase the levodopa dosage to control the symptoms in those patients who had previously required dosage increases to control the symptoms (p>0.05, 95%CI). Improvement was noted with UPDRS total score(39% while on state, 48% while off state) and Hoehn and Yahr stage(39% while on state, 42% while off state). Unilateral pallidotomy produced statistically significant improvement in symptoms for patients with advanced Parkinson' disease for whom medical therapy had failed(p<0.001, 95% Cl). Conclusion : After unilateral pallidotomy there were no statistically significant increase in the total dose of levodopa equivalents, and if needed, the patients were able to tolerate larger doses without experiencing adverse effects.

Background/Aims: To evaluate the effect and safety of Godex(hepadif+PMC, diphenyl-dimethyl-dicarboxylate) in 95 patients with chronic liver disease, a prospective randomized double blind controlled clinical trial of a short-term(8 weeks) therapy with Godex was performed in a total 95 patients with chronic hepatitis who was diagnosed by liver biopsy or recently have a abnormal serum transaminase(ALT and/or AST) concentrations during longer than 6 months. Methods : In this clinical trial, 95 patients with chronic hepatitis patients were enrolled and allocated by a table of random digits in three groups. 32 patients received 150mg/day of PMC(control group), 30 patients received low dose of Godex(low-dose group, PMC 150mg+hepadif 600mg/day) and 33 patients received high dose of Godex(high-dose group, PMC 150mg+hepadif 900mg/day) orally for 8 weeks, and they were followed until 2 weeks without drugs to evaluate rebounding phenomenon of liver enzymes. We evaluate the effect and safety by biochemical laboratory test variables such as liver enzymes and clinical observed data at each visit date such as before(0) and 4, 8 weeks after drug treatment and 2 weeks after 8 weeks treatment. Compliance and side effects were evaluated at the same time. Results : After 4 weeks-treatment of Godex, the percentage of decrease of serum ALT levels within normal range in the low-dose and high-dose groups are about 63.6 and 80.8%, respectively and were significantly(p<0.05) lower than that of control group, 29.6%. Otherwise, after 8 weeks-treatment of Godex, those of low-dose and high-dose groups are about 54.6 and 88.5%, respectively and were significantly(p<0.05) lower compared of control group, 44.4% and that of high-dose group were more significant than low-dose group. But after 2 weeks without drugs, the rebounding phenomenon of serum ALT levels were not different within three groups and adverse effects were negligible and transient during 10 weeks. Conclusions : It is suggested that Godex is more effective and safe than PMC in the short-term treatment of chronic liver disease in Korean patients, but further evaluation about efficacy and safety of Godex for adequate duration of treatment in the large population of patients are needed.

Background : The disposition kinetics of ketoprofen into synovial fluid was estimated to predict the time course of ketoprofen concentration in synovial fluid in patients with arthritis. Methods : After repeated oral doses of ketoprofen 100 mg twice daily, ketoprofen concentrations of plasma and synovial fluid were determined at steady-state by high performance liquid chromatography(HPLC) in 17 arthritic patients. Plasma pharmacokinetic parameters were estimated from one compartmental open model and the penetration pharmacokinetic parameters into synovial fluid were estimated from nonlinear fitting to the effect compartment model using $NONMEM^{\circledR}$. Results: At steady-state, the observed peak concentrations of plasma and synovial fluid were $4.6{\pm}3.2{\mu}g/ml\;and\;2.4{\pm}1.9{\mu}g/ml$ at 2 hours and 5 hours after the last dose, respectively. Plots of plasma ketoprofen concentration against synovial concentration showed anticlockwise hysteresis, suggesting the time delay in the distribution of ketoprofen into synovial fluid from plasma. The estimated average rate constant for the ketoprofen loss from synovial $fluid({\kappa}_{co})$ was $0.16\;h^{-1}$. From the simulation of ketoprofen concentration curves, the predicted $C_{max}$ of synovial fluid was corresponded to 76.6 % of the plasma $concentration(1.44\;{\mu}g/ml\;vs\;1.881{\mu}g/ml)$ and time lag of $T_{max}$ between both fluid spaces was estimated to 3.1 hours. Conclusions : These results suggest that the time course of ketoprofen concentration in synovial fluid is different from plasma concentration-time profile after systemic administration of ketoprofen. The effect compartment model approach appears to be useful to predict the kinetics of ketoprofen in synovial fluid from the plasma data.

Background: The policy of separating prescription and dispensation of drug was implemented on July 1,2000 in Korea according to a revised pharmaceutical legislation and there have been considerable conflicts and confusions related with generic substitution under this new system. So this study was conducted to examine the patients' risk perceptions, attitudes, and behaviors for generic substitution and related factors with them. Methods : Subjects were 428 patients who visited two primary clinics, three secondary and one tertiary hospitals located in Seoul and Kyunggido. The subjects received self-administered questionnaire about risk perceptions, knowledges, attitudes, and behaviors for generic substitution. The perceived risk for generic substitution was measured using a 11-pointed differential scale(more than five, five and less than five points were categorized as high, mid and low in terms of risk perceptions for the generic substitution, respectively). Data were analysed for the related factors with risk perceptions and behaviors for generic substitution using Chi-square test and logistic regression analysis. Results : The percentages of subjects who perceived that generic substitution was riskier than dispensation as brand name drugs prescribed by physicians, and who had actually experienced generic substitution were 74.8%, and 38.3%, respectively. The attitudes and actual behaviors for generic substitutions were significantly associated with risk perception for the generic substitution(P<0.05). The adjusted Odd's ratio of risk perceptions for the generic substitution as a function of age, patients using primary clinic and patients with chronic disease was 0.969(95% CI, 0.943-0.996), 1.958(95% CI, 1.082-3.546) and 2.296(95% CI, 1.090-4.115), respectively ( P<0.05). Conclusion : This study suggested that patients' risk perceptions be related with attitudes and behaviors for generic substitution and some medical factors may affect the risk perception for generic substitution. So physicians are encouraged to discuss the risk and safety of generic substitution with patients. Especially, physicians need to pay much attention to the patients with chronic diseases because they have been shown to perceive generic substitution to be safe blindly.