선형혼합모형을 활용한 생물학적 동등성 분석

안형미,이영조,유경상,An, Hyungmi,Lee, Youngjo,Yu, Kyung-Sang 한국통계학회 2015 응용통계연구 Vol.28 No.2

생동성 시험과 같은 임상약리학분야의 연구는 일반적으로 한 개체 내에서 반복하여 측정된 자료구조를 사용하므로 선형혼합모형을 이용하여 분석하는 것이 보편적이다. 이러한 모형에서 랜덤효과는 개체 내 관측 자료 사이의 상관관계를 설명하고, 공분산행렬은 개체-내 변동을 설명한다. 생동성 분석은 두 약물의 약동학적 변수인 Cmax와 AUC의 기하평균비에 대한 90% 신뢰구간이 동등성 한계인 [0.8, 1.25] 범위에 드는지 알아보는 분석으로, 고정효과에는 시기, 순서군, 치료효과를, 랜덤효과에는 개체효과를 가지는 선형혼합모형을 이용하여 분석한다. 이러한 분석이 적용된 실제 예를 살펴보기 위하여 레보플록사신 연구의 자료를 활용하였다. Linear mixed models are commonly used in the clinical pharmaceutical studies to analyze repeated measures such as the crossover study data of bioequivalence studies. In these models, random effects describe the correlation between repeated outcomes and variance-covariance matrix explain within-subject variabilities. Bioequivalence analysis verifies whether a 90% confidence interval for geometric mean ratio of Cmax and AUC between reference drug and test drug is included in the bioequivalence margin [0.8, 1.25] performed using linear mixed models with period, sequence and treatment effects as fixed and sequence nested subject effects as random. A Levofloxacin study is referred to for an example of real data analysis.

Voriconazole Therapeutic Drug Monitoring is Necessary for Children with Invasive Fungal Infection

강현미,강수영,조은영,유경상,이지원,강형진,박경덕,신희영,안효섭,이현주,최은화,이환종,Kang, Hyun Mi,Kang, Soo Young,Cho, Eun Young,Yu, Kyung-Sang,Lee, Ji Won,Kang, Hyoung Jin,Park, Kyung Duk,Shin, Hee Young,Ahn, Hyo Seop,Lee, Hyunju,Choi, The Korean Society of Pediatric Infectious Disease 2014 Pediatric Infection and Vaccine Vol.21 No.1

목적: 본 연구는 소아 환자들에서 voriconazole 치료적 약물 농도 모니터링의 임상적 의의를 분석하고자 하였다. 방법: 2010년 7월부터 2012년 6월까지 서울대학교병원에 입원한 18세 이하의 소아 환자들 중, 침습성 진균감염증에 대해 voriconazole 치료를 받은 증례를 후향적 의무기록 분석을 통해 분석하였다. 본 연구에 포함된 총 28명의 환자 중 14명이 약물 농도 모니터링을 받았으며, 143개의 혈중 농도 측정 값을 분석하였다. 모든 환자들에게서 치료 효과 및 독성 증상 발현 여부를 파악하였다. 결과: 143개의 혈중 농도 측정 값 중 53.1%에서 치료적 범위(1.0-5.5 mg/L) 내에 들었고, 같은 용법으로 치료받았더라도 높은 혈중 농도 변동성(high variability)을 보였다. 약물 농도 모니터링을 받았던 군(TDM 군)과 받지 않았던 군(non-TDM 군)에서 각각 14명 중 9명(64.3%)이 독성 증상을 나타냈는데, TDM 군에서 신경학적 증상(n=2, 14.3%) 및 간기능 장애(n=8, 57.1%)는 높은 voriconazole 혈중 농도(>5.5 mg/L)를 보인 환자들에게서 나타났다. 반면, 시각 장애는 혈중 농도가 치료적 범위 내에 있을 때 발현하였다(1.18 mg/L, 3.9 mg/L). TDM 군에서 non-TDM 군에 비하여 독성 증상으로 인하여 약물을 중단했던 빈도가 낮았다(0.0% vs. 18.2%, P =0.481). 치료 시작 6주 후 치료 효과를 분석해본 결과 TDM 군의 57.2%에서 치료에 대한 반응을 보였으나, non-TDM 군에서는 14.3%에서 치료 반응을 보였다(P =0.055). 최종 치료효과 분석에서는 TDM 군의 21.4%에서 치료 반응을 보였으나, non-TDM 군의 14.3%에서 치료 반응을 보였다(P =0.664). TDM 군에서 치료 시작 첫 6주 동안 혈중 약물 농도를 분석했을 때 67.0% 이상에서 치료적 범위 내에 들었으나, 치료 기간 전체를 봤을 때에는 45.5%에서 치료적 범위 내에 들었다. 결론: 소아에서 voriconazole 사용 시 치료적 약물 농도 모니터링을 통하여 치료 목표를 효과적으로 달성하고, 독성이 나타나는 것을 예방할 수 있다. Purpose: To determine the clinical significance of voriconazole therapeutic drug monitoring (TDM) in the pediatric population. Methods: Twenty-eight patients with invasive fungal infections administered with voriconazole from July 2010 to June 2012 were investigated retrospectively. Fourteen received TDM, and 143 trough concentrations were analyzed. All 28 patients were assessed for adverse events and treatment response six weeks into treatment, and at the end. Results: Out of 143 samples, 53.1% were within therapeutic range (1.0-5.5 mg/L). Patients administered with the same loading (6 mg/kg/dose) and maintenance (4 mg/kg/dose) dosages prior to initial TDM showed highly variable drug levels. Adverse events occurred in 9 of 14 patients (64.3%) in both the TDM and non-TDM group. In the TDM group, voriconazole-related encephalopathy (n=2, 14.3%) and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (n=8, 57.1 %) occurred with serum levels in the toxic range (>5.5 mg/L), whereas blurred-vision (n=2, 14.3%) occurred within the therapeutic range (1.18 mg/L and 3.9 mg/L). The frequency of voriconazole discontinuation due to adverse events was lower in the TDM group (0.0% vs. 18.2%, P =0.481). Overall, 57.2% of the patients in the TDM group versus 14.3% in the non-TDM group showed clinical response after 6 weeks (P =0.055), whereas 21.4% in the TDM group versus 14.3% in the non-TDM group showed response at final outcome (P =0.664). In the TDM group, >67.0% of the serum levels were within therapeutic range for the first 6 weeks; however 45.5% were within therapeutic range for the entire duration. Conclusion: Routine TDM is recommended for optimizing the therapeutic effects of voriconazole.

건강 자원자에서 레베셀$^{\circledR}$주(DDB-S)의 안정성, 약동학적 특성평가를 위한 제 1상 임상시험

정재용,임형석,배균섭,유경상,홍경섭,조주연,이소영,문전옥,이치오,장인진,신상구,Chung, Jae-Yong,Lim, Hyeong-Seok,Bae, Kyun-Seop,Yu, Kyung-Sang,Hong, Kyoung-Sup,Cho, Joo-Youn,Yi, So-Young,Moon, Jun-Ok,Lee, Chi-Oh,Jang, In-Jin,Shin, Sang- 대한임상약리학회 2001 臨床藥理學會誌 Vol.9 No.2

Background : Low solubility and poor oral absorption have been major problems of DDB(Dimethyl Dime-thoxy Biphenylate), the liver protection agent. The purpose of the study was to evaluate safety, tolerablilty, and pharmacokinetics of DDB-S(Dimethoxybiphenylmonocarboxylate hydro-chloride) which was the newly developed soluble injectable form of DDB. Method : Single dose trial was conducted in 24 healthy Korean subjects with single blind, randomized, placebo controlled parallel-group design( 4 groups : 7.5, 15, 30, 60mg). DDB-S was administrated by intravenous infusion during 60 minutes. Serial blood and urine sample were collected till 24 hours after the drug administration. Plasma concentrations were assayed by HPLC. Pharmacokinetic parameters were analyzed by noncompartmental methods. Results : Total 13 cases of adverse events from 7 subjects were reported. All the events were mild, temporary, and spontaneously resolved. There were no differences in dose normalized AUC, dose normalized Cmax, CL, Vd, Tmax, Fe, $CL_R$ and elimination rate constant between groups. Linear regression analysis confirmed PK linearity within this dose range. Half of the dose$(49.86{\pm}10.97%)$ was excreted as an unchanged form through kidney. Conclusion : DDB-S was safe in Korean healthy subjects. It showed linear pharmacokinetic characteristics. Phase II clinical study for patients will be conducted.

건강한 한국인 자원자에서 테가세로드(Tegaserod) 반복 투여에 의한 안전성 및 약동학 평가

정재용,임형석,홍경섭,배균섭,유경상,조주연,이소영,고재욱,장인진,신상구,Chung, Jae-Yong,Lim, Hyeong-Seok,Hong, Kyoung-Sup,Bae, Kyun-Seop,Yu, Kyung-Sang,Cho, Joo-Youn,Yi, So-Young,Ko, Jae-Wook,Jang, In-Jin,Shin, Sang-Goo 대한임상약리학회 2003 Translational and Clinical Pharmacology Vol.11 No.2

Background: Tegaserod is a selective partial agonist at the $5HT_4$ receptor. Tegaserod belongs to a new class of agents in development for the treatment of functional motility disorders of the gastrointestinal(GD tract. This Phase I clinical study was conducted to evaluate the safety and pharmacokinetics(PK) of tegaserod in Korean for bridging foreign clinical data. Methods: A randomized, double blind, placebo controlled, multiple oral dosing(2 mg, 6 mg, twice a day for 7 days) study was conducted in 32 healthy Korean volunteers(M:F=16:16). Serial blood samples for pharmacokinetic analysis were taken. Safety evaluation was performed by adverse event monitoring, physical examination including vital signs, ECG and clinical labororatory analysis. Results: Plasma concentration of tegaserod reached peak levels $1.0{\sim}1.5$ hours after single and multiple dose administration and declined with a terminal half life of about 12 hours. PK parameters of 2 mg group were not calculated well due to low plasma concentration. Tegaserod showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. There were no gender differences in PK parameters. Neither serious nor dose-limiting adverse events were observed. PK of tegaserod in Koreans was comparable to Caucasian data. Conclusion: Tegaserod was found to be safe and showed similar PK characteristics to Caucasians. This study demonstrates comparability between Korean and Caucasian healthy subjects in the PK of tegaserod and supports the use of Caucasian data in the evaluation of PK, safety, and efficacy for Korean patients.

추체외로 증상에 따른 항정신병 약물 복용량과 음성 특성의 상관관계 분석

이수빈,김서영,김혜윤,김의태,유경상,이호영,이교구,Lee, Subin,Kim, Seoyoung,Kim, Hye Yoon,Kim, Euitae,Yu, Kyung-Sang,Lee, Ho-Young,Lee, Kyogu 한국음향학회 2022 韓國音響學會誌 Vol.41 No.3

본 논문은 항정신병 약물의 복용량에 따른 음성 특징의 상관관계 분석을 수행하였다. 항정신병 약물의 대표적 부작용 중 하나인 추체외로 증상(ExtraPyramidal Symptoms, EPS) 발생에 따른 음성 특징의 패턴을 알아보기 위하여, 문장 개발을 통해 한국어 기반 추체외로 증상 음성 코퍼스를 구축하였다. 수집된 자료는 추체외로 증상 군과 비 추체외로 증상 군으로 나누어 음성 특징 패턴을 조사하였으며, 특히 추체외로 증상 군의 높은 음성 특징 상관관계를 보였다. 또한, 발화 문장의 종류가 음성 특징 패턴에 영향을 미친다는 것을 확인할 수 있었으며, 이를 통해 음성 특징을 기반한 추체외로 증상의 조기 발견 가능성을 기대해볼 수 있었다.

건강한 한국인 자원자에서 바데나필 단회 투여 후 내약성 및 약동학적 특성에 관한 연구

김석의,이승환,임경수,임형석,신상구,장인진,유경상,Kim, Seokuee,Lee, SeungHwan,Lim, Kyoung Soo,Lim, Hyeong-Seok,Shin, Sang-Goo,Jang, In-Jin,Yu, Kyung-Sang 대한임상약리학회 2012 臨床藥理學會誌 Vol.20 No.2

Background: Vardenafil is a phosphodiesterase type 5 inhibitor, used in erectile dysfunction. This study aimed to evaluate the pharmacokinetics and tolerability of vardenafil following a single oral administration in healthy male subjects. Methods: A randomized, double-blind, placebo-controlled, single dosing, dose-escalation study was conducted in 30 healthy subjects. A single oral dose of vardenafil or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 5, 10 and 20 mg. Serial blood and urine samples were obtained up to 48 hours for pharmacokinetic analysis. Vardenafil and its metabolite were detected by high performance liquid chromatography tandem mass spectrometry assay. Results: A total of 45 adverse events (AE) were reported in 22 subjects, including 5 AEs from placebo treatment, and all the AEs were mild, except one case of moderate nasal stuffiness. Vardenafil was absorbed after a single oral dose, with the $t_{max}$ of 0.5-1.0 hours. The $C_{max}$ and $AUC_{last}$ were $10.21{\pm}3.68$ ug/L($mean{\pm}SD$) and $18.08{\pm}7.44\;ug{\times}h/L$ in 5 mg dose group, $19.79{\pm}12.13$ ug/L and $38.61{\pm}21.04\;ug{\times}h/L$ in 10 mg dose group and $53.16{\pm}37.01$ ug/L and $110.05{\pm}69.65\;ug{\times}h/L$ in 20 mg dose group. Dose-linearity on $AUC_{last}$ and $C_{max}$ of vardenafil were observed in three dose groups. In all dose groups, the fraction excreted in urine was less than 1%. Conclusion: The vardenafil was tolerable over a single dose range of 5 - 20 mg. The pharmacokinetics of vardenfil after a single oral dose was explored and linear pharmacokinetic characteristics were observed over the dose range of 5 - 20 mg in healthy subjects.

그래프 모델과 중심성 분석을 이용한 당뇨환자의 처방 및 검사결과의 상관관계 분석

유강민(Kang Min Yoo),박성찬(Sungchan Park),이수진(Su-jin Rhee),유경상(Kyung-Sang Yu),이상구(Sang-goo Lee) 한국정보과학회 2015 정보과학회 컴퓨팅의 실제 논문지 Vol.21 No.7

본 논문은 11,938명의 당뇨환자 의료데이터를 그래프 모델로 변환하고 중심성 분석 기법으로 처방과 검사결과 간 상관관계를 추출해내는 과정에 대해 다루고 있다. 관계형 데이터베이스로 저장되어있는 데이터를 RDB2Graph 프레임워크를 사용하여 유의미한 그래프로 변환하였다, 변환된 그래프에 Personalized PageRank를 적용하여 처방과 검사 간 상관관계를 분석했다. 사용된 그래프 모델에는 환자 별 의료기록 모델과 의료 기록의 시간적 간격을 고려한 모델이 있다. 분석 결과 기존의 의학적 지식에 부합하는 상관관계를 다수 발견할 수 있었으며, 본 논문에서는 발견한 상관관계 중 주요 사례를 소개하여 본 분석방법의 유효함을 보인다. This paper presents the results and the process of extracting correlations between events of prescriptions and examinations using graph-modeling and node centrality measures on a medical dataset of 11,938 patients with diabetes mellitus. As the data is stored in relational form, RDB2Graph framework was used to construct effective graph models from the data. Personalized PageRank was applied to analyze correlation between prescriptions and examinations of the patients. Two graph models were constructed: one that models medical events by each patient and another that considers the time gap between medical events. The results of the correlation analysis confirm current medical knowledge. The paper demonstrates some of the note-worthy findings to show the effectiveness of the method used in the current analysis.

그래프 모델을 이용한 당뇨환자의 처방 및 검사결과의 상관관계 분석

유강민(Kang Min Yoo),박성찬(Sungchan Park),이수진(Su-jin Rhee),유경상(Kyung-Sang Yu),이상구(Sang-goo Lee) 한국정보과학회 2014 한국정보과학회 학술발표논문집 Vol.2014 No.12