Population pharmacokinetics or pharmacodynamics is a science researching the variability in drug concentration or effect in a population of patients. The application of population PK/PD methods into drug development and regulation has been expanded for decades. The first step for typical population approach is to develop a population PK/PD model using sparsely sampled data collected from clinical trials. Mixed effect method has been employed to analyze such sparse population data. Mean population parameters and their distribution in relation with patient characteristics(e.g., age, weight, organ function) are given by the population model. Clinical trial simulation is the next step applying the information of population parameters. Researchers can see what the results of various clinical trial scenarios will be like in advance at this simulation step. In this review, three examples of population PK/PD modeling applied to drug development are introduced; 1) Designing Phase II clinical trial using simulated effects from single dose Phase I trial, 2) Approval of a new dosage regimen without clinical trial, 3) Search for quantitative relationship between a biomarker and a surrogate endpoint of diabetes.

Pharmacovigilance is the science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Information sources for pharmacovigilance could be premarketing or postmarketing data from pre-clinical experiments, clinical trials, spontaneous reports, large automated databases, pharmacoepidemiologic studies, and meta-analysis studies. Spontaneous reporting data playa key role to identify signals for marketed drugs. Steps in the spontaneous adverse event signaling process consist of signal detection phase and signal evaluation phase, and involve various statistical methods. Through record linkage of large existing automated databases by individual identifiers, it is possible to conduct longitudinal researches on drug safety issues in large population. Carefully designed and conducted pharmacoepidemiologic studies are important tools in pharmacovigilance. Case-control studies and cohort studies are widely used to confirm the causality between drugs and adverse events. In this paper, we discussed possible data sources for pharmacovigilance and introduced some useful methodological approaches. Evidence-based decisions through these methods should be effectively distributed to healthcare professionals, patients and media.

Background and Objectives : Electronic documents provide cost-time benefits over paper documents generated during clinical trials. Electronic document standards and guidelines for management, exchange, and submission of clinical trial data are now being prepared by international standard organizations. As a step from paper based clinical trial toward electronic clinical trial, it is essential to keep up with international electronic document standards and guidelines. Methods: We introduce electronic document standards and guidelines, which were discussed at the 18th Drug Information Association Electronic Document Annual Meeting. We first present the necessity of standards and guidelines related to electronic documents of clinical trial data. Next, we introduce international standard organizations including ICH, CDISC, and regulatory agency like US FDA, and their standards and guidelines. Results : ICH has developed guidelines for the registration of pharmaceuticals for human use. It has proposed two electronic document standards, Individual Case Safety Report and Electronic Common Technical Documents. US FDA posted final rules and drafts describing submission of data for new drug application in electronic format. CDISC develops models for submitting clinical trial data, operating institutions performing clinical trials, and generating metadata from statistical data. Conclusion: The standards and guidelines related with electronic documents of clinical trial data presented by international standard organizations will playa key role in the era of electronic clinical trials. It is recommended to join the standardization movement while standards and guidelines are actively being prepared.

Background : Cytochrome P450 (CYP) 2C8 is the major enzyme that metabolizes many xenobiotics, including the anti-cancer drug paclitaxel and anti-diabetic drug rosiglitazone. Genetic polymorphisms of the human CYP2C8 gene were identified in Korean population, and their effects on the phenotype were evaluated on the basis of the in vivo pharmacokinetics of rosiglitazone. Methods : We surveyed genetic variations in all exons, exon-intron junctions, and promoter region of human CYP2C8 gene from 306 unrelated healthy Koreans by using fluorescence two-dimensional gene scanning (TDGS) and sequence analyses. Pharmacokinetic parameters of rosiglitazone after 8 mg single dose in relation to the corresponding polymorphisms were estimated. Results : Genetic analysis revealed the existence of eleven single nucleotide polymorphisms (SNPs). Two synonymous SNPs, three non-synonymous SNPs and one nucleotide deletion were identified in the coding region, two SNPs in intron, and three SNPs in promoter region. Allele frequencies of 324A>G, 37OC>T (Rl24W) in exon2, 475delA (CYP2C8*5) in exon3, 917T>C (L306P) in exon6, 1171C>A (L391M), and 123OC>T in exon8 were 0.005, 0.002, 0.002, 0.002, 0.002, and 0.26, respectively. Three common SNPs, -411T>C, -370T>G, and -271C>A in the 5'-flanking region were frequent at 0.382, 0.330, and 0.116, respectively. The functional significance of the two upstream polymorphisms (CYP2C8*1C and * lD) and R124W and 475delA alleles was investigated in pharmacokinetics of rosiglitazone. Pharmacokinetic characteristics of rosiglitazone were not different in single heterozygous subject for either 370C>T or 475delA and in homozygous subjects for CYP2C8*lC and CYP2C8*lD, compared with homozygous wild type subjects. Conclusion : Although several genetic polymorphisms for CYP2C8 were identified in Koreans, there was no evidence that either upstream and non-synonymous SNPs gave rise to altered pharmacokinetics of rosiglitazone.

연구배경 및 방법: 차세대 위산분비 저해제(gastric acid-pump antagonist) revaprazan의 인체 내분비기능에 대한 영향력을 평가하기 위하여 13명의 건강한 한국인 남성 지원자를 대상으로 revaprazan 200mg 또는 위약을 1일 1회 7일간 투여하기 전후로 내분비 기능을 평가하는 이중 눈가림법 무작위배정 교차시험 (double blind, randomized, crossover design)을 시행하였다. 투약 전후 혈청 tri-iodothyronine (T3), thy­roxine (T4), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) 농도를 측정하였고, 시상하부-뇌하수체 호르몬 분비계에 대한 평가를 위해 thyrotropin-releasing hormone (TRH) 및 luteinizing hormone-releasing hormone (LHRH) 자극검사가 시행되었다. 연구결과 : $T_3,\;T_4$, TSH, FSH, LH의 위약투여에 대한 revaprazan 투여 시 평균비(90% 신뢰구간)는 1.04 (0.9% - 1.081), 1.00 (0.947 - 1.044), 1.27 (0.973 - 1.570), 0.92 (0.833 - 1.009), 0.97 (0.867 - 1.075)이었다. TRHLHRH 자극에 따른 TSH 와 LH 혈중농도변화는 위약과 revaprazan 투여기 간에 차이가 통계적으로 유의하지 않았다 (p > 0.05, repeated-measures ANOVA). 결 론 : 치료용량에서 revaprazan의 갑성선 및 성선호르몬분비계에 대해서는 영향을 미치지 않을 것으로 평가되었으며, 환자에서 사용 시 내분비계 이상반응에 대해서는 안전할 것으로 기대되나, 시판 후 조사 통한 추가적인 안전성 자료 수집 이 필요할 것으로 사료된다.

Background: Gatifloxacin, a broad-spectrum fluoroquinolone antibiotic, has been used for the treatment of pneumonia, acute sinusitis, acute exacerbation of chronic bronchitis, and urinary tract infections. Compared to other quinolones, gatifloxacin shows higher activity and has a low incidence of photosensitivity reaction. The purpose of this study was to evaluate the interchangeability between gatifloxacin single tablet of 200 mg and two tablets of 100 mg, by comparing the relative bioavailability of the two different formulations. Methods : This study was conducted as an open-labeled, randomized, two-way crossover design in 16 healthy male subjects. Subjects were separated into two groups (groups A and B, 8 subjects per group). Subjects in group A were administered gatifloxacin 200 mg single tablet orally and one week later gatifloxacin 100 mg two tablets orally. Subjects in group B were administered in the opposite sequence in the same manner. Serial blood samples were collected till 48 hours after drug administration. Plasma concentrations of gatifloxacin were analyzed by reversed phase HPLC. Pharmacokinetic parameters were calculated by noncompartmental methods and ANOVA was used for statistical analysis. Results: The ratio of $AUO_{last}$ of gatifloxacin 200 mg single tablet to gatifloxcin 100 mg two tablets was $1.00\;{\pm}\;0.15$ $(mean\;{\pm}\;SD)$ The ratio of $C_{MAX}$ was $0.98\;{\pm}\;0.24$ $(mean\;{\pm}\;SD)$. There were no sequence, period or treatment effects on $AUO_{last}$ and $C_{max}$ by ANOVA. The 90% confidence intervals for the ratios of geometric means based on log-transformed $AUO_{last}$ and $C_{max}$ between the two regimens were 0.93-1.06 and 0.85-1.06, respectively. Conclusions : We concluded that gatifloxacin 200 mg single tablet and gatifloxacin 100 mg two tablets show similar bioavailability, and that they can be administered interchangeably.

Background : Androgenetic alopecia (AGA) is an androgen-dependent hereditary disorder. Compared to the past, a rising number of patients with AGA have been seeking treatment. Oral finasteride and topical minoxidil are the only drugs approved, till now, by the Food and Drug Administration of USA for the treatment of this condition. Unfortunately, these treatment options are not satisfactory. Therefore, it has been necessary to develop new drugs for this psychologically frustrating disease. Methods : This is a 24-week, double-blinded, placebo-controlled, randomized clinical trial to determine whether a new topical treatment, HDMHG0401-10, is effective in showing clinical improvements in patients with AGA. A total of 41 men (23-49 years old) with AGA were treated either with the topical HDMHG0401-10 solution or a placebo, twice daily. Efficacy was evaluated by phototrichogram as well as patients' subjective and investigator's photographic assessments for change in hair density. Results : After 24 weeks of therapy, topical HDMHG0401-10 treatment resulted in significant improvement from the baseline in total hair count and showed to be significantly superior to the placebo in terms of hair loss count. There was no statistically significant difference in patients' and investigator's hair growth ratings between the HDMHG0401-l0 treated and placebo groups. HDMHG0401-l0 was generally well tolerated. Conclusion : We have confirmed the efficacy of HDMHG0401-10 in treating AGA in men, by an objective assessment with phototrichogram. No evidence of major side effects was seen.

Background : Specialized and continuous educational program is needed for investigators. A questionnaire survey was performed to examine current status of educational experience, preferred forms and contents for educational program and certification system, prior to development of investigator educational and certification programs. Methods : Developed questionnaires were posted to 738 clinical investigators in October 2005. The questionnaire consisted of questions about demographics, clinical trials experience, educational program experience, and preferred educational and certification program. The analysis included investigators who participated in at least one clinical trial within past 3 years. Results : A total of 122 subjects was responded to the survey (16.5% response rate). Among the total subject 96 (78.7%) had participated in at least one clinical trial within past 3 years and all analyses included only the 96 subjects. Forty three percent had experience to be educated related to clinical trials and over ninety percent had intention to participate in the educational program for investigators. Preferred educational contents for clinical investigators both for basic and advanced course were subject protection and consent, regulation, clinical trial design, statistics and data management, protocol development, randomization, and blinding. Eighty three percent of subjects preferred short-term intensive course with 3 days or less. Investigators participated in any education program once or more agreed to necessity of certification system more than non-participants (p=0.002). University, research center or academic society was preferred for Institution for certification (55.8%). Conclusion : Educational program for investigators specialized by diverse time period and level has tobe developed. Certification for investigators seems to be necessary to improve research capacity and to standardize quality continuously.

Background : There's very limited educational programs for clinical research nurses (CRNs) in Korea. This study was aimed to identify current status of educational experience, preferred educational and certification program of CRNs Methods : This was cross-sectional descriptive study with fifty three CRNs and forty CRAs who were conveniently selected. Data were collected with questionnaires including demographics, educational experience, and preferred educational and certification program of CRNs by mail or e-mail. Results : Sixty six percent had experience to be educated related to the clinical research or clinical trials, and ten programs were popular. Preferred educational contents for CRNs were monitoring & reporting adverse events, completing case report form (CRF), reviewing protocol for basic course, and regulation, making a manual, and research methodology for advanced course. Short-term intensive course with twenty eight or twenty nine hours and on-site education were preferred. Over ninety percents thought certification program was necessary. New potential agency such as association of clinical research professionals was recommended to be good for organizing the certification program. The best qualification to have certification was taking educational course and passing the test. Conclusion : The rate of being educated related to the clinical research or clinical trials among the CRNs was not so high. Therefore, we need to increase the rate and develop educational programs with considering the preferred contents, time period, and operation method for CRNs. Certification for CRNs seems to be necessary to improve the qualify and satisfaction of CRNs, and independent agency can be helpful to organize it.

The current status and preferred model of clinical trial education program and certification system for clinical trial pharmacist(CTP) were evaluated through a questionnaire survey. The questionnaire sheets were sent to 150 CTPs in 100 medical centers where clinical trials are permitted by KFDA. The survey was conducted for 3 months from October 1 to December 31, 2005. The 63 CTPs from 46 medical centers respondents our questionnaire (response rate was 42% for CTP, 46% for medical center).92.1% of the respondents were female, and 58.7% were ranged from 31 to 40 years old (average 34.7+/-6.0). Their working periods at hospital of 0-4.9, 5-9.9 and 10-14.9 were 28.6%, 30.2% and 26.7%, respectively. But 90.5% of them have been working as CTPs for less than 5 years. 84.1% of them have experiences to participate in any clinical trial education program, but only 49.1% of participants were satisfied with the education program. The main reason of low satisfaction was the lack of systematic program and absence of certification system of CTP in Korea. The number of medical centers providing clinical research related services was 44, which were consisted of 14 secondary hospitals, 5 tertiary general hospitals and 25 tertiary university hospitals. Among 44 medical centers, 16 hospitals (36.4%) have clinical trial centers, of which 6 hospitals (37.5%) have pharmacies in clinical trial centers. The contents for the future education program were selected by the survey. And also all 63 CTPs wanted to participate at the well organized clinical trial education program, they preferred midterm (about 3 months) (46%) and short-term periods (39.7%). The 92.1% of CTPs wanted to introduce the certification program of CTPs who took the required clinical trial education program. They also preferred KFDA (50.8%) and academic associations (15%) as operating organization for the certification program. From the results of these study, it was found that the well organized clinical trial education program is needed to increase the quality of CTPs, and also surveyed data will be used to develop the contents of training materials.