Biotech drugs which have been approved since 1980's take a major portion in the pharmaceutical industry with increasing number of drugs in the market. Because ADME of biotech drugs differ from that of small molecules, many of the drugs show non-linear pharmacokinetic behaviors and PK analysis using non-compartmental methods may also give misleading parameter values. As macromolecules, the distribution may be confined to the extracellular space, however, receptor mediated endocytosis and circulation through lymphatic vessels may change the distribution profile. Another uniqueness in the PK of biotech drugs is that the drug targets (receptors) act as an elimination mechanism of the drug. Therefore, the elimination may be influenced by the effect (pharmacodynamics) of drugs and vice versa. In the development of biotech drugs, mechanism based PK-PD modeling based upon the understanding of such unique characteristics will be helpful to avoid mistakes in the clinical trial design.

Background: Losartan is a nonpeptide angiotensin II receptor antagonist used in hypertension. The objective of this study was to evaluate the bioequivalence of two losartan formulations, $Sarlotan^{(R)}$ 50 mg tablet (Chong Kun Dang, Pharmaceutical Corp. Seoul, Korea) as a test drug and $Cozaar^{(R)}$ 50 mg tablet (MSD Korea, Co., Ltd., Seoul, Korea) as a reference drug. The bioavailability was evaluated based on the requirement of 20% deviation at a power of 80%. Methods: This study had a randomized, open-label, 2-period, crossover design. There was a 12-hour treatment period for each formulation, with a 1-week washout period between formulations. Each subject received one 50 mg tablet of the reference or test formulation of losartan. Blood samples were obtained during the 12-hour period after the dose in each treatment period. Concentrations of losartan in plasma were analyzed using a liquid chromatography system with tandem mass-spectrometric detection (LC/MS/MS). The primary pharmacokinetic parameters were $C_{max}$ (maximum concentration) and $AUC_t$ (area under the concentration-time curve from time 0 to the last sampling time). Results: A total number of 36 healthy malevolunteers participated in the study and 33 volunteers completed both treatment periods (age range, 19-29 years; mean height, 176.3 cm mean weight, 67.8 kg). The 90% CIs for the geometric mean ratios of the pharmacokinetic parameters (test:reference drug) were 0.96 ~ 1.07 for $AUC_t$ and 0.83 ~ 1.21 for $C_{max}$ lying within the range of the 80% to 125% bioequivalence criterion. Conclusion: The obtained results indicated that pharmacokinetic exposure to $Sarlotan^{(R)}$ tablet was bioequivalent to that of $Cozaar^{(R)}$ tablet.

Leflunomide는 기존의 DMARD에 비해서 구조와 작용기전이 다른 새로운 류마티스 치료제로 최근 류마티스 관절염의 치료에 많이 사용되고 있다. 본 약제의 사용으로 인한 범혈구감소증과 동반된 빈혈은 드물게 보고 되어 왔으나, 범혈구감소증이나 혈전성 미세혈관병증과 동반되지 않은 용혈성 빈혈이 발생한 증례는 보고되지 않았다. 저자들은 leflunomide 사용 후 용혈성 빈혈이 발생한 36세 여자 환자를 경험하였기에 문헌 고찰과 함께 보고하는 바이다.

Backgrounds: Atorvastatin which has a highly variable pharmacokinetic profileoften shows double peaks. However, in most cases it has been regarded as a noise or assay error. In this study we compared 4 different absorption models (zero order, $1^{st}$ order, combined and parallel absorption model) to determine which model best describes the absorption process. Methods: Plasma atorvastatin data of 57 healthy subjects from two bioequivalence studies were used. Concentrations were measured up to 48 hours after drug administration. Mixed effect analysis to compare the 4 absorption models was performed using NONMEM version 6.0. Results: The absorption process was best described bycombined absorption model. CL/F and Vd/F were 400L/hand 779L, respectively, and KA and D were $0.09\;hr^{-1}$ and $0.53\;hr^{-1}$, respectively. Conclusion: Although the combined absorption model did not fully describe the double peaks, this study demonstrated that absorption models other than simple first or zero order absorption are necessary to describe the double peaks phenomenon.

Background: According to the economic prosperity, the Korean pharmaceutical market is growing fast accompanied by the increment of the multinational clinical trial studies. Under these circumstances, lots of promotional policies and plans have been enforced by the Korean government specifically through a project name as 'Strategy Development for the Establishment of Infrastructure and Promotion of Clinical Studies in Korea' in 2003. In regard to evaluate the efficacy of the project and the extent of the accomplishment, we performed a follow-up study in comparison to the year 2003. Methods: The study was performed for 6 months at the qualified, ninety-nine medical institutions. Specific information was gathered by surveys or data-collections to investigate the correlations among facilities, staffs, and education programs if any changes happened during the study period. Also, the study was designed to understand if there is any improvement on infrastructures after initiating the government's plan. All the data were processed by a statistical program for the analyses of the rank, frequency, and the relationship between the variables. Results: The average response rate was 77.8% and revealed that the number of workforce was increased associated with the promotional policies of the government. However, the scarcity of both allocated-time and trained professionals for the clinical studies as well as the inadequate level of facilities were selected as the most troublesome factors in participating the multinational study projects. Conclusion: The follow-up study reveals that all institutions were successful to enlarge their capabilities when focusing their resources on the infrastructures in accordance with the governmental enforcements. In addition, we suggest that the remaining problems could be diminished through fast decisions on investments, correcting actions on imbalances, complementary measures on the governmental activities.

Background: Bupropion is an antidepressant and a non-nicotine aid used in smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine and inhibits the neuronal reuptake of dopamine. Although several in vitro study demonstrated that CYP2D6 activity was inhibited by bupropion, there is no in vitro study that directly reports the inhibitory effects of bupropion on human major CYP isoforms. In the present study, we investigated the inhibitory effects and mechanism-based inactivation potencies of bupropion for human CYP2C19, CYP2D6, CYP2A6 and CYP3A4 activities. Methods: In vitro study was performed using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. The specific activities for human CYP isoforms included in this study were S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), testosterone 6-hydroxylation (CYP3A4), and coumarin 7-hydroxylation (CYP2A6). Results: Bupropion competitively inhibited S-mephenytoin 4'-hydroxylase ($Ki\;=\;1.631{\pm}0.544\;{\mu}M$). and bufuralol 1'-hydroxylase ($Ki\;=\;1.017{\pm}0.284\;{\mu}M$). The IC50 values for inhibition of CYP2C19 (coumarin, $1\;{\mu}M)$ and CYP2D6 (bufuralol, $1\;{\mu}M$) index reaction by bupropion were $3.36\;{\mu}M$ and $6.45\;{\mu}M$, respectively. CYP3A4 and CYP2A6 activities were not significantly inhibited by bupropion. Furthermore, bupropion did not reveal a mechanism-based inactivation of CYP2C19 and CYP2D6. It was clearly shown that CYP2C19 and CYP2D6 were not inactivated by bupropion in a time and concentration dependent manner. Conclusions: Bupropion showed inhibitory effects on CYP2C19 and CYP2D6 activities. These results suggest that bupropion would affect the pharmacokinetics of clinically used drugs that are metabolized by CYP2C19 and CYP2D6.

Background: The number of clinical trials which have been performed within Korea is increasing accompanied by the enlargement of the various responsibilities of each Institutional Review Board (IRB) in the way of providing adequate and on-time managerial involvements on the studies. Many confounding factors of each study can influence on the results with which delaying the final reports, or extending the review times associated with research-periods, or adjusting the alterations. Even though these factors were closely related to the results being managed by the IRBs, no in-depth research have been implemented to elucidate the correlations between these factors and the results necessitates IRBs' managements. Methods: Study subjects were selected and analyzed retrospectively in a University hospital's database. About 190 study projects which had been completed during 2005 to 2007 were retrieved and the characterized factors were classified into seven categories. Each category was analyzed and tested statistically by SAS program. Results: It is revealed that a large portion of the factors was subjected to the study profiles. The review-time showed extended tendency in the subjects which used medications (P=0.0174) required approval (P=0.0009) in phases I II III (P<0.0001) initiated by sponsors (P<0.0001) and with duration of 1 to 2 years (P=0.0442). Prior to submitting IRB, correction-times were multiplied specifically on the study subjects that used medications (P<0.0001) required approvals (P<0.0001), underwent phase I II III (P<0.0001) reviewed twice (P=0.0074) initiated by sponsors (P<0.0001) exceeded 2 years of period (P<0.0001) and required modifications before the submission (P=0.0001). Conclusion: The clinical study projects characterize by 'medication-used', 'sponsor-initiated', 'approval-required', 'duration period of 1 to 2 years', and 'under phase I II III' required thorough concerns and investigations from the beginning stage to reduce the time of review by the IRBs. Studies lasted more than 2 years entailed preparation of the sudden alterations to prevent the study duration. A new further study is necessary to analyze the frequency and the causes of the alterations in the study proposals.

Background: Over the past decade, pharmaceutical companies have introduced a number of initiatives to boost the productivity of clinical trials. In clinical trials, this can take to reduce costs and durations of that are being considered in applying information technology. One of these initiatives has been the rollout of electronic data capture (EDC) systems, which allow patients and researcher to enter their trial information directly, either in electronic diaries or online systems. The utilization rate of the EDC in the United States is 41.5%, and similar trends can be seen in 40.5% in Japan. Objectives: Currently, the adoption of EDC in Korea is also getting increased, so the current status of EDC application should be assessed in clinical trials. The aim of this study was identified in present status of EDC system and to improvements to develop it. Method: The survey of participants has been accomplishment in a clinical research coordinator workshop and e-CRF System workshop, which was held in a University Hospital, located in Seoul. The main questionnaire items were 14 including the career of EDC system. Totally, 109 responses were classified by fields of clinical trials study, and comparison analyzed each questionnaire items. Result: The survey of participants has been separated pharmaceutical company participants (39.4%), contract research organization or clinical research associate participants (26%), investigator (research coordinator) (24%), and other participants (10.6%). Current EDC System applied Phase III(40.0%) and will plan to use of system Phase I(34.5%), Phase II(16.7%) Conclusion: EDC systems are increasingly applied for clinical trials and current status of EDC system was assessed in this study. To increase the adoption of the EDCs, the related regulations should be developed, and also decision makers need to understand the importance of information technology in clinical trials.