The Asian Pharmacometrics Network: The historical background, establishment, objectives and roles, and recent activities

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A Study on the Deterioration and On-line Diagnosis Equipment for Surge Protective Devices

본 논문은 서지호보기용 온라인 진단장치의 설계 및 제작에 관하여 연구하였다. 전기적 특성 변화 및 건전성 기준을 제시하기 위해서 표준 뇌 충격전류(8/20μs) 10 kA를 인가하여 가속열화 실험을 수행하였다. 실험결과를 바탕으로 누설전류, 기준전압 및 제한전압을 측정할 수 있는 온라인 진단장치를 제작하였다. 누설전류 측정회로는 저잡음증폭기 및 클램프형 영상변류기로 설계하였고, 기준전압 측정회로는 선형제어부, 연산부, 누설전류 측정부 및 직류고전압 발생부로 구성하였다. 제한전압 측정회로는 서지발생부 및 커플링 회로로 제작하였다. 제안한 진단장치와 독립 실험계와의 측정값 차이는 3% 미만으로 정확한 진단이 가능하다.This thesis dealt with the deterioration and an on-line diagnosis equipment for surge protective device(SPD). An accelerated aging test was carried out using a 8/20μs standard lightning impulse current to analyze the changes of electrical characteristics and to propose the diagnostic parameters and the criterion for deterioration of metal oxide varistor(MOV) which is the core component of SPDs. The leakage current of MOV increased whereas the reference voltage decreased with the aging process. When they changed more than 10% compared with the initial values, the deterioration was accelerated. On the other hand, since there was little change in the clamping voltage, it could not be used to evaluate the deterioration but its waveform could be applied to verify the operation of varistor. In addition, the criterion of soundness MOV was proposed. Based on the experimental results, an on-line diagnosis equipment for SPD was fabricated, which can measure total leakage current, reference and clamping voltage. The leakage current measurement circuit is composed of a low-noise amplifier and a clamp type zero-phase current transformer(ZCT). A linear controller, a data acquisition module, and a HVDC supply were used in the measurement of reference voltage. The clamping voltage measurement circuit consists of a surge generator and a coupling circuit. In a calibration process, measurement error of the protype equipment was less than 3%. From the experimental results, it was confirmed that the proposed equipment is avaliable to diagnose the SPD condition in operation.목 차 ⅰ 그림 및 표 목차 ⅲ Abstract ⅴ 제 1 장 서 론 1 제 2 장 관련 이론 3 2.1 서지의 발생 및 보호 3 2.2 산화아연형 바리스터 7 2.3 열화진단기술 11 제 3 장 가속열화 실험 14 3.1 서지발생장치 14 3.2 실험계 20 3.3 전기적 특성 변화 22 제 4 장 서지보호기 진단장치 30 4.1 회로 설계 30 4.2 진단장치 제작 36 4.3 적용 실험 38 제 5 장 결 론 42 참 고 문 헌 4

Effects of SLCO1B1 and SLCO1B3 Genetic Polymorphisms on Valsartan Pharmacokinetics in Healthy Korean Volunteers

Purpose: This study aimed to examine OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) on the pharmacokinetics of valsartan. Twenty-five subjects were genotyped for 16 single-nucleotide polymorphisms of the SLCO1B1 and SLCO1B3 genes. Methods: After a single dose of 160 mg of valsartan was orally administered to healthy male volunteers, drug concentrations were assayed up to 48 h. The 25 subjects were genotyped for 16 single-nucleotide polymorphisms (SNPs) of the SLCO1B1 and SLCO1B3 genes. Subjects were classified into groups according to their SLCO1B1*1B haplotype; 23 subjects were carriers of SLCO1B1*1B and two subjects were included in the reference group with SLCO1B1*1A/*1A. Alternations of the splicing factor-binding site pattern caused by the given mutation were evaluated with the Human Splicing Finder (HSF) 3.1. Results: The subjects who carried SLCO1B1*1B showed a 2.3-fold higher clearance than those without the *1B haplotype. Mean Cmax and AUCinf were reduced by 45% and 54%, respectively, in the SLCO1B1*1B genotype group compared to the reference group with the *1A/*1A genotype (p < 0.01). The carriers of the rs4149153 T allele of SLCO1B3 had a 27% lower mean Cmax and a 1.5-fold higher Vd compared to homozygotic CC carriers (p < 0.05). In a combined analysis of SLCO1B1 and SLCO1B3, subjects not carrying SLCO1B1 *1B and carrying SLCO1B3 rs4149153 T allele showed a 1.6-fold higher clearance than those with the other genotypes, whereas mean Cmax and AUClast were reduced by 35% and 42%, respectively (p < 0.05), in the subjects. HSF 3.1 analysis showed that rs4149153 could cause alterations of the acceptor splice site (TAAATACTAAAGAC to TAAATATTAAAGAC) with scoring change (from 72.57 to 71.92, difference = -0.9). Conclusion: It was found that plasma exposure to valsartan is significantly decreased in SLCO1B1*1B carriers and carriers of the rs4149153 T allele of SLCO1B3, possibly as a result of increased hepatic uptake.ope

A Pharmacometric Model to Predict Chemotherapy-Induced Myelosuppression and Associated Risk Factors in Non-Small Cell Lung Cancer

Chemotherapy often induces severe neutropenia due to the myelosuppressive effect. While predictive pharmacokinetic (PK)/pharmacodynamic (PD) models of absolute neutrophil count (ANC) after anticancer drug administrations have been developed, their deployments to routine clinics have been limited due to the unavailability of PK data and sparseness of PD (or ANC) data. Here, we sought to develop a model describing temporal changes of ANC in non-small cell lung cancer patients receiving (i) combined chemotherapy of paclitaxel and cisplatin and (ii) granulocyte colony stimulating factor (G-CSF) treatment when needed, under such limited circumstances. Maturation of myelocytes into blood neutrophils was described by transit compartments with negative feedback. The K-PD model was employed for drug effects with drug concentration unavailable and the constant model for G-CSF effects. The fitted model exhibited reasonable goodness of fit and parameter estimates. Covariate analyses revealed that ANC decreased in those without diabetes mellitus and female patients. Using the final model obtained, an R Shiny web-based application was developed, which can visualize predicted ANC profiles and associated risk of severe neutropenia for a new patient. Our model and application can be used as a supportive tool to identify patients at the risk of grade 4 neutropenia early and suggest dose reduction.ope

Population Pharmacokinetics of Primaquine in the Korean Population

While primaquine has long been used for malaria treatment, treatment failure is common. This study aims to develop a population pharmacokinetic model of primaquine and its metabolite, carboxyprimaquine, and examine factors influencing pharmacokinetic variability. The data was obtained from a clinical study in 24 Korean subjects randomly assigned to normal and obese groups. The participants received primaquine 15 mg daily for 4 days and blood samples were collected at day 4. Pharmacokinetic modeling was performed with NONMEM and using simulations; the influences of doses and covariates on drug exposure were examined. A minimal physiology-based pharmacokinetic model connected with a liver compartment comprehensively described the data, with CYP450 mediated clearance being positively correlated with the body weight and CYP2D6 activity score (p < 0.05). In the simulation, while the weight-normalized area under drug concentration for primaquine in the obese group decreased by 29% at the current recommended dose of 15 mg, it became similar to the normal weight group at a weight-normalized dose of 3.5 mg/kg. This study has demonstrated that the body weight and CYP2D6 activity score significantly influence the pharmacokinetics of primaquine. The developed model is expected to be used as a basis for optimal malaria treatment in Korean patients.ope

Predicting the longitudinal changes of levodopa dose requirements in Parkinson's disease using item response theory assessment of real-world Unified Parkinson's Disease Rating Scale

Item response theory (IRT) has been recently adopted to successfully characterize the progression of Parkinson's disease using serial Unified Parkinson's Disease Rating Scale (UPDRS) measurements. However, it has yet to be applied in predicting the longitudinal changes of levodopa dose requirements in the real-world setting. Here we use IRT to extract two latent variables that represent tremor and non-tremor-related symptoms from baseline assessments of UPDRS Part III scores. We show that relative magnitudes of the two latent variables are strong predictors of the progressive increase of levodopa equivalent dose (LED). Retrospectively collected item-level UPDRS Part III scores and longitudinal records of prescribed medication doses of 128 patients with de novo PD extracted from the electronic medical records were used for model building. Supplementary analysis based on a subset of 36 patients with at least three serial assessments of UPDRS Part III scores suggested that the two latent variables progress at significantly different rates. A web application was developed to facilitate the use of our model in making individualized predictions of future LED and disease progression.ope