Annual Reports on External Quality Assessment for Clinical Laboratories in Korea (2013) Annual Report on

Annual Reports on External Quality Assessment for Clinical Laboratories in Korea (2013) http://dx.doi.org/10.15263/jlmqa.2014.36.1.12 Annual Report on the External Quality Assessment of Therapeutic Drug Monitoring and Testing for Drugs of Abuse in Korea (2013) Tae-Dong Jeong 1, Gum-Gyoung Gu 1, Sail Chun 1, and Jeong-Ho Kim 2, as Therapeutic Drug Monitoring Subcommittee, The Korean Association of Quality Assurance for Clinical Laboratory 1 Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine; 2 Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Corresponding author: Sail Chun Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-4513 Fax: +82-2-478-0884 E-mail: sailchun@amc.seoul.kr We performed two trials on the external quality assessment for therapeutic drug monitoring (TDM) and testing for drugs of abuse (DOA) organized by the Therapeutic Drug Monitoring (TDM) subcommittee of the Korean Association of Quality Assurance for Clinical Laboratories (KAQACL) in 2013. In each trial, two levels of control material for TDM, and positive and negative control material for DOA testing, were requested from candidate institutions. The number of participating laboratories was 106 and 105 for the first and second trials, respectively. The average number of drug items was 5.6 per institution. The most commonly tested substances were valproic acid, followed by digoxin, phenytoin, carbamazepine, and tacrolimus, in descending order. The mean inter-laboratory coefficients of variation for low- and high-level control materials were 9.3% and 6.7%, respectively. The most widely used TDM analysers were Architect i System (Abbott Diagnostics, USA), followed by Cobas Integra (Roche Diagnostics, Switzerland) and Cobas c501 analyser (Roche Diagnostics). The number of participating laboratories for DOA testing increased by 30% compared with that in 2012. We received 100% and 98.2% correct answers from the participating DOA laboratories in each trial, respectively. In the external quality assessment for TDM by the TDM subcommittee of KAQACL in 2013, the overall performance of TDM was similar to previous years and the inter-laboratory precision was improved compared with that in 2012. Continuous quality improvement for TDM testing is needed through participation in a proficiency-testing program. (J Lab Med Qual Assur 2014;36:12-22) Key Words : Quality assurance, Laboratory proficiency testing, Drug monitoring piss: 1225-097X eiss: 2288-7261 서론 대한임상검사정도관리협회약물검사분과위원회는 1995 년부터혈중치료적약물농도 (therapeutic drug monitoring) 검사에대한신빙도조사를시작하였고, 2007 년부터는남용약물 (drug of abuse) 검사에대한신빙도조사를실시하고있다 [1-4]. 저자들은 2013 년실시되었던치료적약물농도검사및남용 약물검사의신빙도조사결과를분석하여보고하고자한다. 재료및방법 1. 정도관리물질및대상기관총 2회에걸쳐치료적약물농도검사및남용약물검사신빙도조사를실시하였다. 제1회차신빙도조사대상정도관리물질 12 Copyright 2014 The Korean Association of Quality Assurance for Clinical Laboratory

은 2013 년 6월 3일발송하였다. Lyphocheck TDM Control (Bio-Rad Laboratories, Hercules, CA, USA) level 1 (13-01) 및 level 3 (13-02) 두종류의물질을총 107 개참여기관에발송하였고 Lyphocheck whole blood (WB) control (Bio- Rad Laboratories) level 1 (13-01 WB) 및 level 3 (13-02 WB) 두종류물질은 cyclosporine, tacrolimus, sirolimus 검사를시행하는총 63개기관을대상으로발송하였다. 그리고 Liquicheck Qualitative Urine Toxicology Control (Bio- Rad Laboratories) negative (13-01 urine) 및 positive (13-02 urine) 두종류물질을 30개기관에발송하였다. 제2회차정도관리물질발송은 2013 년 9월 24일에시행하였다. Drug Control (Randox Laboratories, orthern Ireland, UK) level 1 (13-03) 및 level 2 (13-04) 두종류의물질을총 107 개참여기관을대상으로발송하였고 Lyphocheck whole blood control (Bio-Rad Laboratories) level 1 (13-03 WB) 및 level 2 (13-04 WB) 두종류의물질을 cyclosporine, tacrolimus, sirolimus 검사를시행하는총 63 개기관을대상으로발송하였다. 그리고 Liquicheck Qualitative Urine Toxicology Control (Bio-Rad Laboratories) negative (13-03 urine) 및 positive (13-04 urine) 두종류의물질을 30개기관에발송하였다. 2. 신빙도조사약물종목 2013년도대한임상검사정도관리협회약물검사분과에서실시한치료적약물농도검사신빙도조사약물종목은 acetaminophen, amikacin, amitriptyline, carbamazepine, digoxin, free phenytoin, free valproic acid, gentamicin, lithium, methotrexate, phenobarbital, phenytoin, salicylate, theophylline, tobramycin, valproic acid, vancomycin, cyclosporine, tacrolimus (FK-506), sirolimus 등총 20항목으로제1회와제2회차모두동일한약물을대상으로하였다. 남용약물검사신빙도조사종목은 3,4-methylenedioxymetha mphetamine, 9-COOH-11-nor- 9-THC, benzoylecgonine, d-amphetamine, d-methamphetamine, ethanol, lysergic acid diethylamide, methadone, methaqualone, free morphine, nordiazepam, nortriptyline, oxazepam, phencyclidine, propoxyphene, secobarbital 등 16 항목으로제 1회와제2회차모두동일한약물을대상으로하였다. 3. 정도관리물질제조방법정도관리물질제조는제조사의지침대로시행하도록하였다. 1회차에발송된치료적약물농도검사정도관리물질 Lyphocheck TDM control (Bio-Rad Laboratories) 은검사 당일 Class-A 용적피펫 (volumetric pipet) 을사용하여탈이온수 5.0 ml를넣어용해시켜실온에 15분간세워둔후검사전혼합하여사용하도록하였다. 2회차에발송된 Drug Control (Randox Laboratories) 은검사당일 Class-A 용적피펫을사용하여탈이온수 5.0 ml를넣어용해시켜실온에 30분간세워둔후검사전혼합하여사용하도록하였다. Lyphocheck whole blood control (Bio-Rad Laboratories) 은검사당일 Class-A 용적피펫을사용하여탈이온수 2.0 ml를넣어용해시켜실온에 20분간세워둔후검사전혼합하여사용하도록하였다. 남용약물검사물질은액상으로전처리없이검사하도록하였다. 4. 수탁기관인정기준본분과위원회에서정한치료약물농도검사의수탁기관인정기준은다음과같았다. 첫째, 특정회차에서약물종목중 unacceptable 인약물종목이 2건이하이어야한다. 단장비별 peer group 이 5기관이하일경우 unacceptable 인약물종목이 3건이하이어야한다. 둘째, 참여한약물종목중해당약물종목이 2회연속으로모든정도관리물질결과 ( 연속된 4개검사 ) 가 unacceptable 인종목이없어야한다. 단장비별 peer group 이 5기관이하일경우해당약물종목이 3회연속으로모든정도관리물질결과 ( 연속된 6개검사 ) 가 unacceptable 인종목이없어야한다. Unacceptable 의기준은약물검사분과 acceptable 판정허용범위기준을벗어난경우를말한다. 약물종목별허용기준은다음과같다. Acetaminophen, amikacin, amitriptyline, carbamazepine, cyclosporine, free phenytoin, free valproic acid, methotrexate, salicylate, sirolimus, tacrolimus (FK-506), vancomycin 등의허용기준은 ±3SD 또는 ±10% 이고, gentamicin, phenobarbital, phenytoin, theophylline, tobramycin, valproic acid 등의약물허용기준은 ±25% 이다. Digoxin 은 ±20% 또는 0.2 ng/ ml 이고 lithium 은 ±20% 또는 0.3 mmol/l 이다. 5. 결과분석및통계약물농도의보고단위및소수점유효숫자를약물검사분과위원회에서제시한것으로하지않고임의대로한기관에대해서는본위원회제시안을참고하여일괄환산처리하였다. 또한검사장비코드를기록하지않은기관은 2012 년과동일코드로처리하였으며통계분석은각검사종목별로장비의차이를고려하지않은전체통계와각장비별 (peer group) 로평균, 표준편차, 표준편차지수 (standard deviation index) 값을내되, 표준편차지수값이 +3.0 또는 -3.0 을벗어나는기관의결과값 www.jlmqa.org J Lab Med Qual Assur 2014;36:12-22 13

은제외하고다시평균, 표준편차, 및표준편차지수값을계산하였다. 단, 참여기관이단일기관인경우통계에서제외하였다. 또한각군별로변이계수 (coefficient of variation), 최젓값및최댓값을산출하였다. 결과분석및통계처리는 Microsoft Excel 2010 (Microsoft, Redmond, WA, USA) 프로그램과 Microsoft Access 2010 (Microsoft) 프로그램을사용하였다. 결과 1. 신빙도조사참여기관및검사종목 1회차는 107 기관중 106 기관이회신하여회신율 99.1%, 2 회차는 107 기관중 105 기관이회신을하여회신율 98.1% 였다. 기관당평균검사종목수는 5.6 종목이었다. 가장많은기 관에서회신한약물농도검사종목은 valproic acid 86.4%, digoxin 70.6%, phenytoin 55.1%, carbamazepine 50.9% 등 4종목으로서 50.0% 이상의기관에서응답하였다. 다음으로 tacrolimus 49.5%, vancomycin 48.1%, theophylline 47.7%, cyclosporine 43.9% 순이었고, 10% 미만의회신을보인종목은 sirolimus, amikacin, acetaminophen, gentamicin, salicylate, tobramycin, free phenytoin, free valproic acid 등의종목이었다. Amitriptyline 과 pirimidon 두약물의응답률은 1회차, 2회차모두 0% 였다 (Table 1). 2. 검사장비이용현황치료약물농도감시검사장비는 Architect i System (Abbott Diagnostics, Abbott Park, IL, USA) 의사용률이 37.4% 로가 Table 1. Response rate of the 2013 therapeutic drug monitoring proficiency testing by the Korean Association of Quality Assurance for Clinical Laboratories, including the previous three years Test substances Year 2010 2011 2012 2013 Response rate 1st 2nd 1st 2nd 1st 2nd 1st 2nd 2013 2010 2012 Acetaminophen 7 7 7 7 7 7 7 6 6.1 6.5 Amikacin 12 12 10 10 9 8 8 7 7.0 9.4 Amitriptyline 0 0 0 0 0 0 0 0 0.0 0.0 Carbamazepine 67 65 60 59 58 55 55 54 50.9 56.0 Cyclosporine 45 46 46 47 46 47 47 47 43.9 42.6 Digoxin 83 83 80 80 78 77 76 75 70.6 74.0 Ethosuximide 1 1 0 0 0 0 0 0 0.0 0.3 Free phenytoin 3 4 3 2 2 2 2 2 1.9 2.5 Free valproic acid 1 2 1 1 1 1 2 1 1.4 1.1 Gentamicin 8 7 7 7 7 7 6 5 5.1 6.6 Lithium 31 31 32 31 33 32 33 33 30.8 29.2 Methotrexate 18 17 17 17 17 17 18 18 16.8 15.8 Phenobarbital 49 48 46 46 45 43 43 41 39.3 42.6 Phenytoin 68 65 63 63 62 60 59 59 55.1 58.6 Primidone 1 1 0 0 0 0 0 0 0.0 0.3 Salicylate 5 5 5 5 6 6 5 5 4.7 4.9 Sirolimus - - 8 8 9 9 9 9 8.4 7.8 Tacrolimus 45 47 46 46 51 53 53 53 49.5 44.3 Theophylline 64 64 60 59 56 51 52 50 47.7 54.5 Tobramycin 6 6 6 6 5 5 5 4 4.2 5.2 Valproic acid 91 91 92 92 91 92 93 92 86.4 84.5 Vancomycin 44 45 46 47 48 49 52 51 48.1 42.9 Total of institutions 110 110 108 108 107 107 106 105 26.3 26.8 Values are presented as %. 14 J Lab Med Qual Assur 2014;36:12-22 www.jlmqa.org

장높았고, 그다음으로 Cobas Integra (Roche Diagnostics, Basel, Switzerland), Cobas c501 (Roche Diagnostics) 순이었다 (Table 2). 리튬 (lithium) 검사의경우검사방법이나장비의사용에있어서전체리튬검사기관의 78.1% 인 25기관에서이온선택전극 (ion selective electrode) 법이이용되고있었고, 건식슬라이드 (dry slide) 법을사용하는기관은 15.6% 인 5기관, 6.3% 인 2기관에서는원자흡광광도계 (atomic absorption spectrometer) 법을사용하였다. 3. 치료적약물농도검사치료적약물농도검사의검사실간평균변이계수는저농도 9.3% 였고고농도 6.7% 였다 (Table 3). 약물종류별신빙도조사결과는장비를고려하지않은전체참가기관의평균, 표준편차및변이계수와장비를고려한평균, 표준편차및변이계수 Table 2. Distribution of the instruments used for therapeutic drug monitoring for the Korean Association of Quality Assurance for Clinical Laboratories proficiency testing during 2013 ame of instrument Year 2010 2011 2012 2013 Abbott Architect i System 14.5 21.1 33.2 37.4 Roche Cobas Integra 16.9 17.6 19.5 19.9 Roche Cobas c501 (Cobas 6000) 6.5 6.9 6.0 6.5 Roche/Hitachi Systems 5.1 5.7 5.8 5.7 Abbott AxSym 25.4 19.5 8.2 5.5 Siemens Diagnostics Advia Centaur 2.0 1.8 2.6 3.9 Siemens Diagnostics Viva-E 5.5 5.2 3.2 3.4 Siemens Diagnostics Dimension 4.0 3.5 4.0 2.7 Beckman UniCel DxC Synchron 2.3 2.4 2.4 2.3 Abbott TDx/TDxFLx 7.0 3.3 2.3 2.3 Toshiba chemistry analyzer 2.8 2.5 2.1 1.8 Waters LC/MS/MS 0.5 1.6 1.1 1.2 AVL Scientific - 0.6 0.8 1.0 Beckman Synchron LX Systems 1.8 1.7 1.8 0.9 ova CRT/ucleus - 0.9 0.8 0.9 Roche Cobas e601/e170 1.0 0.9 0.8 0.9 Abbott Architect c system/aeroset 1.8 0.6 0.5 0.7 Vitros 5,1 FS Chemistry System 0.2 0.9 0.8 0.6 Agilent technologies 0.2 0.0 0.5 0.5 Siemens Diagnostics Vista - - 0.4 0.5 Radioimmunoassay 0.3 0.0 0.3 0.3 ova - 0.2 0.2 0.2 Siemens Diagnostics Advia Centaur CP 0.1 0.1 0.2 0.2 Konelab - - 0.3 0.2 Roche 9100 Series (ISE Mode) - 0.1 0.5 0.2 Varian (AAS) - 0.2 0.2 0.2 Vitros DT60 II Chemistry System - 0.2 0.2 0.1 BioMerieux VIDAS 1.0 1.0 1.1 0.1 Other methods 0.3 0.5 0.3 0.1 Total 100.0 100.0 100.0 100.0 Values are presented as %. www.jlmqa.org J Lab Med Qual Assur 2014;36:12-22 15

Table 3. Mean inter-laboratory for each substance using low- and high-level control materials during the last 5 years Substance Inter-laboratory for low-level control materials of Average 2008 to 2012 2012 (1st) 2012 (2nd) 2013 (1st) 2013 (2nd) Inter-laboratory for high-level control materials of Average 2008 to 2012 Acetaminophen 7 26.3 30.8 8.2 3.8 3.0 7 4.7 3.1 4.0 2.4 2.3 Amikacin 8 8.0 10.2 4.8 5.2 13.0 8 6.8 5.1 8.1 6.3 5.4 2012 (1st) 2012 (2nd) Amitriptyline - - - - - - - - - - - - Carbamazepine 55 6.9 6.1 7.4 6.6 5.6 55 6.9 7.3 7.4 6.2 6.8 Cyclosporine 47 11.4 11.1 13.6 11.9 10.5 47 9.5 10.1 10.4 9.9 9.5 Digoxin 76 16.3 13.6 15.4 15.4 25.2 77 8.8 9.8 7.3 9.1 10.8 Free phenytoin 2 11.7 10.1 0.8 9.5 4.9 2 20.7 24.2 15.5 12.9 7.1 Free valproic acid 1 - - - - - 1 18.2 - - Gentamicin 6 6.7 6.1 7.9 4.7 4.0 7 8.1 6.2 8.2 7.2 10.2 Lithium 33 15.2 11.7 11.4 10.4 18.1 32 13.6 10.6 12.2 10.3 6.7 Methotrexate 18 7.5 3.9 8.7 4.3 4.1 17 6.9 6.3 4.3 2.9 5.3 Phenobarbital 43 6.8 6.7 6.3 6.9 7.2 43 7.4 6.7 6.9 6.7 5.5 Phenytoin 59 6.1 5.4 5.0 7.2 5.4 60 5.0 4.6 4.6 7.5 6.4 Primidone - - - - - - - 7.0 - - Salicylate 5 8.4 10.7 9.5 5.9 6.7 6 2.5 2.2 2.0 1.1 0.5 Sirolimus 9 13.2 10.7 4.4 13.6 12.0 9 13.2 13.5 13.0 8.8 7.9 Tacrolimus 53 18.3 9.2 19.1 9.1 7.4 53 9.3 9.1 7.8 7.3 7.3 Theophylline 52 5.9 5.0 5.0 4.4 4.6 51 5.3 5.2 5.9 4.9 4.9 Tobramycin 5 20.3 26.5 20.4 39.5 11.6 5 15.3 15.1 13.4 16.1 2.3 Valproic acid 93 7.5 8.4 8.4 7.9 6.3 92 5.8 6.0 5.0 4.8 3.5 Vancomycin 52 7.1 8.5 6.9 6.4 11.7 49 8.6 7.8 9.4 7.6 8.3 Total mean 11.3 10.8 9.1 9.6 9.0 9.2 8.5 8.1 7.3 6.1 Abbreviation:, laboratories. Values are presented as %. 2013 (1st) 2013 (2nd) 를구분하여요약하였다 (Tables 4 7). 2013 년시행된치료적약물농도검사신빙도조사에참여한모든기관은수탁기관인정기준을만족하였다. 4. 남용약물검사남용약물검사신빙성조사에참여한기관수는 1차 25기관, 2차 26기관이었다. 13-01 (urine), 13-02 (urine), 13-03 (urine) 검체는모든기관에서정답을보고하였다. 13-04 (urine) 검체는 d-methamphetamine 두기관, free morphine 과 lysergic acid diethylamide 은각각 1개의기관에서오답을보고하였다 (Table 8). 남용약물검사의신빙도조사결과모든기관이수탁기관인정기준을만족하였다. 고찰 대한임상정도관리협회약물검사분과위원회의치료적약물농도검사신빙도조사사업참여기관수는사업이시작된이후 2007 년까지꾸준히증가하다가이후유사한수준을보였다. 2013 년참가기관수는 1회차에 106 기관, 2회차에 105 기관으로 2012 년에 107 기관에비해 1 2 기관감소하였다. 2013 년평균회신율은 98.6% 로 2012 년 100% 에비해 1.4% 감소하였다. 기관당평균검사종목수는 5.6 종목으로 2008 2012 년최근 5개년간평균 5.7 종목과유사하였다. 최근 5년간가장많은기관에서회신한약물종목은 valproic acid 였다. 대체적으로각기관에서회신한약물종목은예년과유사한수준이었다. Cyclosporine, vancomycin, tacrolimus 등약물들의응답률은최근 3년 (2010 2012) 간평균응답률에비해증가 16 J Lab Med Qual Assur 2014;36:12-22 www.jlmqa.org

Table 4. Proficiency testing results for the therapeutic drug monitoring of acetaminophen, amikacin, carbamazepine, and digoxin during 2013 Test substances Method Acetaminophen All methods (Cobas Integra) 13-01 13-02 13-03 13-04 7 9.86±0.38 3.83 7 111±2.63 2.36 6 24.8±0.75 3.03 6 201±4.71 2.34 Amikacin All methods 8 4.8±0.25 5.22 8 26.7±1.69 6.34 7 3.59±0.47 13 7 26.7±1.44 5.38 Cobas Integra 4 4.8±0.22 4.5 4 25.4±0.61 2.38 4 3.8±0.36 9.37 4 26.3±0.64 2.43 Carbamazepine All methods 55 3.08±0.2 6.59 55 14.9±0.92 6.16 54 2.89±0.16 5.6 54 15.8±1.07 6.81 Architect i 13 3.25±0.11 3.23 13 15.3±0.64 4.22 14 2.79±0.06 2.2 14 14.9±0.31 2.07 Cobas Integra 13 2.91±0.1 3.28 13 14.7±0.95 6.42 13 2.92±0.11 3.74 13 17±0.66 3.86 Abbott AxSym 7 3.1±0.27 8.74 7 14.8±1.16 7.88 6 2.88±0.16 5.56 6 15.1±0.42 2.81 Cobas 6000 6 2.98±0.1 3.3 6 14.9±0.78 5.23 6 2.88±0.2 7.08 6 15.7±0.81 5.2 Hitachi 6 2.65±1.3 49.2 6 13.6±2.47 18.1 6 3±0.27 8.94 6 15.7±0.67 4.26 Centaur 3 3.13±0.15 4.88 3 16.3±1.06 6.49 3 3±0.2 6.67 3 16.6±1.36 8.16 DxC Synchron 2 2.7±0.14 5.24 2 13.7±0.99 7.23 2 2.9±0.57 19.5 2 14.7±0.42 2.89 VIVA-E 2 3.15±0.21 6.73 2 14.8±0.57 3.82 2 3.15±0.07 2.24 2 16.5±2.33 14.2 Toshiba 2 3.15±0.21 6.73 2 14.9±0.64 4.29 2 3.05±0.07 2.32 2 15.9±0.21 1.34 Digoxin All methods 76 0.67±0.1 15.4 76 2.64±0.24 9.13 75 0.42±0.11 25.2 75 2.97±0.32 10.8 Architect i 25 0.6±0.03 4.91 25 2.53±0.07 2.73 26 0.32±0.04 11.7 26 2.76±0.06 2.33 Cobas Integra 14 0.71±0.09 13.3 14 2.55±0.16 6.3 14 0.45±0.08 16.9 14 2.89±0.17 6.06 Centaur 7 0.77±0.1 12.3 7 2.93±0.2 6.75 7 0.49±0.07 14.2 7 3.26±0.27 8.29 Cobas 6000 6 0.67±0.05 7.75 6 2.48±0.08 3.03 6 0.45±0.05 12.2 6 2.77±0.15 5.44 Abbott AxSym 5 0.68±0.11 16.1 5 2.76±0.38 13.7 6 0.48±0.04 8.33 6 3.67±0.11 2.92 Modular E-170 5 0.7±0.07 10.1 5 3.16±0.15 4.8 4 0.5±0.14 28.3 4 2.85±0.26 9.28 Hitachi 4 0.7±0.16 23.3 4 2.53±0.26 10.4 3 0.63±0.15 24.1 3 3.27±0.42 12.7 DxC Synchron 2 0.65±0.07 10.9 2 2.55±0.07 2.77 2 0.6±0.14 23.6 2 3.05±0.07 2.32 VIVA-E 2 0.5±0.14 28.3 2 2.6±0.14 5.44 2 0.45±0.07 15.7 2 3.15±0.21 6.73 Abbreviation:, laboratories. www.jlmqa.org J Lab Med Qual Assur 2014;36:12-22 17

Table 5. Proficiency testing results for the therapeutic drug monitoring of free phenytoin, gentamicin, lithium, methotrexate, phenobarbital, and phenytoin during 2013 Test substances Method Free phenytoin All methods (Cobas Integra) 13-01 13-02 13-03 13-04 2 0.89±0.08 9.53 2 4.11±0.53 12.9 2 0.58±0.03 4.88 2 4.66±0.33 7.12 Gentamicin All methods 6 2.95±0.14 4.67 6 7.98±0.58 7.24 5 2.24±0.09 3.99 5 8.04±0.82 10.2 Architect i 3 2.83±0.06 2.04 3 8.13±0.21 2.56 3 2.2±0.1 4.55 3 8.4±0.92 10.9 Cobas Integra 2 3.1±0 0.02 2 7.35±0.21 2.89 2 2.3±0 0.03 2 7.5±0.14 1.89 Lithium All methods 33 0.51±0.05 10.4 33 2.16±0.22 10.3 33 0.48±0.09 18.1 33 1.74±0.12 6.68 AVL Scientific 6 0.56±0.11 19.8 6 2.28±0.23 10 6 0.49±0.06 11.7 6 1.75±0.07 3.92 ova CRT 5 0.49±0.04 7.92 5 2.46±0.1 4 6 0.41±0.04 9.14 6 1.76±0.09 5.21 Cobas Integra 4 0.5±0 0.99 4 2.05±0.1 4.91 4 0.46±0.02 5.41 4 1.68±0.06 3.52 Vitros 5.1 FS 4 0.58±0.07 12.4 4 2.21±0.19 8.58 2 0.7±0 0.01 2 2.15±0.07 3.29 Roche 9100 series 3 0.53±0.02 4.38 3 2.22±0.12 5.38 3 0.47±0.04 9.27 3 1.79±0.12 6.7 Cobas 6000 2 0.48±0.02 4.37 2 1.89±0.01 0.37 2 0.53±0.1 18.7 2 1.74±0.08 4.88 Methotrexate All methods 18 0.39±0.02 4.26 18 8.77±0.26 2.93 18 0.32±0.01 4.06 18 7.37±0.39 5.28 Abbott TDx 14 0.39±0.01 3.73 14 8.89±0.43 4.79 14 0.32±0.01 4.29 14 7.25±0.18 2.5 Cobas Integra 2 0.38±0.02 5.66 2 8.44±0.23 2.77 2 0.33±0.01 4.29 2 7.28±0.04 0.58 Phenobarbital All methods 43 9.33±0.64 6.88 43 50.5±3.39 6.71 41 8.13±0.59 7.19 41 48.5±2.68 5.52 Architect i 16 9.69±0.53 5.47 16 51.8±2.09 4.03 16 8.38±0.27 3.27 16 49.7±1.03 2.07 Cobas Integra 9 9.16±0.21 2.26 9 49.5±1.75 3.53 9 7.97±0.14 1.78 9 48±1.76 3.66 Cobas 6000 5 8.86±0.27 3.05 5 50.2±1.73 3.44 5 8.02±0.76 9.47 5 48.8±2.77 5.67 Abbott AxSym 4 9.13±0.36 3.94 4 47.3±6.05 12.8 3 8.13±0.15 1.88 3 45.1±4.73 10.5 Hitachi 3 9.33±1.6 17.2 3 53.6±5.52 10.3 3 8.53±1.27 14.8 3 52±6.87 13.2 DxC Synchron 2 9.05±0.49 5.47 2 45±0.99 2.2 2 7.25±0.64 8.78 2 43±0.35 0.82 Phenytoin All methods 59 6.8±0.49 7.19 59 23.3±1.74 7.47 59 4.44±0.24 5.43 59 22.5±1.43 6.37 Architect i 22 7±0.21 3.06 22 23.5±0.62 2.66 23 4.54±0.1 2.31 23 22.6±0.52 2.29 Cobas Integra 14 6.6±60.39 5.81 14 23.2±1.82 7.83 14 4.21±0.13 3.16 14 21.8±0.91 4.16 Hitachi 5 7.08±0.08 1.18 5 22.4±0.87 3.87 5 4.48±0.11 2.45 5 23.3±4.14 17.8 Abbott AxSym 5 6.38±0.29 4.62 5 23±1.29 5.62 4 4.53±0.26 5.81 4 21.2±0.7 3.3 Cobas 6000 4 5.88±0.54 9.26 4 21.3±1.43 6.72 4 4.38±0.15 3.43 4 22.8±1.38 6.07 Centaur 3 7.93±0.7 8.85 3 30.2±2.34 7.76 3 5.23±0.35 6.71 3 28.4±3.3 11.6 DxC Synchron 2 6.45±0.07 1.1 2 20.8±0.78 3.75 2 4.3±0.14 3.29 2 22.5±1.41 6.29 VIVA-E 2 6.75±0.78 11.5 2 25.1±0.28 1.13 2 4.25±0.21 4.99 2 23.1±1.91 8.28 Abbreviation:, laboratories. 18 J Lab Med Qual Assur 2014;36:12-22 www.jlmqa.org

Table 6. Proficiency testing results for the therapeutic drug monitoring of salicylate, theophylline, tobramycin, valproic acid, and vancomycin during 2013 Test substances Method Salicylate All methods (Cobas Integra) 13-01 13-02 13-03 13-04 5 5.96±0.35 5.88 5 42.7±0.47 1.1 5 3.44±0.23 6.69 5 37.2±0.18 0.48 Theophylline All methods 52 4.74±0.21 4.43 52 29.3±1.42 4.85 50 5.19±0.24 4.56 50 30.1±1.48 4.93 Architect i 21 4.69±0.21 4.39 21 28.9±1.47 5.09 22 5.17±0.14 2.68 22 29.5±1.04 3.52 Cobas Integra 11 5±0.29 5.87 11 30±1.22 4.08 11 5.38±0.13 2.47 11 31±0.63 2.04 Cobas 6000 4 4.72±0.13 2.66 4 29.5±0.66 2.24 4 5.32±0.19 3.55 4 30.4±0.05 0.16 Hitachi 4 4.75±0.31 6.55 4 29.6±0.57 1.93 4 5.1±0.26 5.06 4 30.2±0.96 3.18 Architect c 2 4.85±0.21 4.37 2 27.3±0.49 1.82 1 4.6±0-1 27.4±0 - DxC Synchron 2 4.35±0.07 1.63 2 28±0.92 3.29 2 4.8±0.14 2.95 2 27.9±0.78 2.79 Centaur 2 4.75±0.07 1.49 2 29.5±0.57 1.92 2 5.2±0.42 8.16 2 33±3.54 10.7 VIVA-E 2 4.8±0 0.03 2 31.6±2.76 8.74 2 5.4±0.14 2.62 2 36.1±3.96 11 Tobramycin All methods 5 0.66±0.26 39.5 5 5.78±0.93 16.1 4 1.65±0.19 11.6 4 7.42±0.17 2.3 Cobas Integra 2 0.6±0 0.03 2 5.5±0 0 2 1.8±0 0.02 2 7.3±0.14 1.94 Valproic acid All methods 93 33.6±2.65 7.88 93 134±6.47 4.81 92 31.1±1.97 6.33 92 143±5.01 3.5 Architect i 30 31.1±1.01 3.25 30 131±3.77 2.86 31 29.6±1.07 3.6 31 144±3.01 2.08 Cobas Integra 19 34.2±0.63 1.84 19 135±3.04 2.25 19 31.3±0.82 2.62 19 142±3.68 2.58 Abbott AxSym 10 34.9±2.47 7.08 10 131±8 6.09 8 32.3±1.58 4.9 8 140±4.34 3.09 Cobas 6000 7 35.1±1.68 4.77 7 139±6.85 4.94 7 32.4±2.3 7.09 7 144±7.16 4.98 Hitachi 6 33.2±3.54 10.7 6 135±8.02 5.92 6 32.2±1.94 6.03 6 143±4.32 3.01 Centaur 5 36.4±1.52 4.17 5 131±5.59 4.28 5 32.2±0.84 2.6 5 137±10.6 7.71 VIVA-E 5 36.8±2.59 7.03 5 141±1.64 1.16 5 34.8±2.68 7.71 5 148±6.44 4.35 DxC Synchron 2 33.5±0.71 2.11 2 135±1.41 1.05 2 29.5±2.12 7.19 2 138±17.7 12.9 Dimension 2 39±1.41 3.63 2 140±19.8 14.1 2 32.5±0.71 2.18 2 142±3.54 2.5 Vancomycin All methods 52 13.5±0.85 6.35 52 79±6.02 7.63 51 4.9±0.57 11.65 51 30.8±2.56 8.3 Architect i 21 13.8±0.55 4.01 21 80.8±2.7 3.34 22 4.6±0.14 3 22 29.6±0.78 2.64 Cobas Integra 13 13.9±0.51 3.65 13 84±8.54 10.2 13 5.5±0.44 8 13 33.3±1.55 4.64 Cobas 6000 4 12.2±0.45 3.71 4 69.2±3.28 4.74 4 5.4±0.62 11.67 4 32.2±2.93 9.11 Abbott AxSym 3 12.8±0.67 5.22 3 75.7±3.38 4.47 2 4.7±1.13 24.07 2 29.4±1.41 4.81 Centaur 2 10.8±0.71 6.55 2 65.5±7.42 11.3 2 4.1±0.21 5.24 2 24.2±1.13 4.68 Dimension 2 13.1±1.27 9.72 2 74.7±9.05 12.1 2 4.4±0.14 3.21 2 28.8±0.64 2.21 Toshiba 2 12.3±0.49 4.04 2 73±2.62 3.59 2 4.3±0.42 9.87 2 30.8±1.91 6.21 Abbreviation:, laboratories. www.jlmqa.org J Lab Med Qual Assur 2014;36:12-22 19

Table 7. Proficiency testing results for the therapeutic drug monitoring of cyclosporine, sirolimus, and tacrolimus during 2013 Test substances Method 13-01 13-02 13-03 13-04 Cyclosporine All methods 47 84.5±10.1 11.9 47 332±32.9 9.93 47 83.7±8.78 10.5 47 316±30 9.49 Architect i 23 88.8±5.6 6.31 23 343±30.1 8.75 23 86.3±7.89 9.14 23 329±27.7 8.43 Dimension 7 85.8±10.6 12.3 7 334±13 3.89 8 84±5.49 6.54 8 321±13 4.06 Abbott AxSym 3 74.4±7.32 9.84 3 294±26.8 9.14 2 88.7±9.97 11.3 2 279±48.2 17.3 Radioimmunoassay 2 77.5±38.9 50.2 2 306±99.7 32.6 2 74±22.6 30.6 2 274±58.7 21.5 Hitachi 2 65.1±5.73 8.8 2 316±20.9 6.63 2 80±4.17 5.22 2 306±16.5 5.38 VIVA-E 2 82.7±3.11 3.76 2 356±5.3 1.49 2 89.8±1.13 1.26 2 317±8.91 2.81 Waters 2 86.1±1.48 1.73 2 315±9.33 2.96 2 80.6±6.86 8.52 2 293±9.33 3.19 Sirolimus All methods 9 4.77±0.65 13.6 9 9.43±0.83 8.79 9 4.87±0.59 12 9 9.23±0.73 7.9 Architect i 4 5.08±0.17 3.37 4 9.97±0.33 3.31 4 5.27±0.3 5.66 4 9.63±0.32 3.33 Waters 3 4.8±0.92 19.1 3 9.43±0.87 9.26 3 4.73±0.7 14.8 3 9.23±1.03 11.1 Tacrolimus All methods 53 4.59±0.42 9.14 53 8.5±0.62 7.26 53 4.65±0.35 7.43 53 10.6±0.77 7.29 Architect i 40 4.66±0.27 5.78 40 8.57±0.47 5.47 44 4.68±0.23 4.92 44 10.6±0.52 4.85 Dimension 3 3.83±0.61 15.9 3 8.33±0.21 2.5 VIVA-E 3 5.07±0.4 7.98 3 9.27±0.55 5.94 3 5.57±1.31 23.5 3 11.1±2.35 21.2 Waters 3 4.53±0.32 7.09 3 8.3±0.1 1.2 3 4.5±0.1 2.22 3 9.53±0.47 4.96 Hitachi 2 2.6±0.85 32.6 2 5.75±2.19 38.1 2 2.8±0.99 35.4 2 7.55±2.47 32.8 Abbreviation:, laboratories. 20 J Lab Med Qual Assur 2014;36:12-22 www.jlmqa.org

Table 8. Drugs of abuse and the number of participating laboratories showing the percentage of correct answers gained in the proficiency testing by the Korean Association of Quality Assurance for Clinical Laboratories during 2013 Test substances Participating laboratories during 2013 13-01 (urine) 13-02 (urine) 1303 (urine) 13-04 (urine) d-methamphetamine 24 (100) 24 (100) 26 (100) 26 (92) d-amphetamine 14 (100) 14 (100) 15 (100) 15 (100) Morphine, Free 19 (100) 19 (100) 20 (100) 20 (95) 9-COOH-11-nor-Δ9-THC 17 (100) 17 (100) 18 (100) 18 (100) Benzoylecgonine 18 (100) 18 (100) 19 (100) 19 (100) Phencyclidine 9 (100) 9 (100) 9 (100) 9 (100) 3,4-Methylenedioxymethamphetamine 7 (100) 7 (100) 8 (100) 8 (100) Oxazepam 3 (100) 3 (100) 4 (100) 4 (100) Secobarbital 2 (100) 2 (100) 2 (100) 2 (100) Methadone 3 (100) 3 (100) 4 (100) 4 (100) ordiazepam 2 (100) 2 (100) 3 (100) 3 (100) Ethanol 2 (100) 2 (100) 2 (100) 2 (100) ortriptyline 2 (100) 2 (100) 2 (100) 2 (100) Lysergic acid diethylamide 1 (100) 1 (100) 2 (100) 2 (50) Propoxyphene 1 (100) 1 (100) 2 (100) 2 (100) Methaqualone 1 (100) 1 (100) 1 (100) 1 (100) Values are presented as number (% of correct answers). 된반면 digoxin, phenytoin, carbamazepine, theophylline, phenobarbital 등의약물들은응답률이감소하였다. 2013 년전체참여기관의 tacrolimus 약물에대한평균응답률은 49.5% 로 2010 2012 년평균응답률 44.3% 에서 5.2% 가상승하여증가폭이가장컸다. 반면응답률감소폭이가장큰약물은 theophylline 으로 2010 2012 년평균응답률이 54.5% 였지만 2013 년응답률은 47.7% 로 6.8% 감소하였다. 약물검사분과에서는각기관에기관별평가를위해서검사장비차이를고려하지않은종목별표준편차지수값과검사장비별표준편차지수값을별도로계산하여보고하였다. 2013 년저농도와고농도정도관리물질의검사실간평균변이계수는각각 9.3%, 6.7% 로최근 5개년의평균검사실간변이계수인저농도 11.3%, 고농도 9.2% 에비해변이계수가감소하여정밀도가향상된소견을보였다. 약물별검사실간변이계수는대체로예년과유사하였다. Cyclosporine 의경우 radioimmunoassay 법을사용하는기관은두기관으로평균검사실간변이계수는 33.7% 였다. 이는 cyclosporine 검사에서참여기관수가동일한다른장비를사용하는기관의평균변이계수 4.3% 보다매우높았다. 그리고 Hitachi 장비를사용하여 tacrolimus 약물농도검사를시행하는검사실의검사실간변이계수는평균 34.7% 로, 장비를고려하지않은전체평균 7.8% 보다높았다. 비록참여기관수가적다고하더라도동일검사법을사용하는검사실간변이계수가큰종목들은정밀도의재평가가필요할것으로판단되었다. 2013 년남용약물검사신빙도조사참여기관수는 1회차 25 기관, 2회차 26기관으로 2012 년 1회차 21기관, 2회차 18기관에비해약 30% 증가하였다. 증가된참여기관은대부분 3 차의료기관의검사실이었다. 남용약물검사신빙도조사정답률은예년과유사하였지만 d-methamphetamine 2기관, free morphine 과 lysergic acid diethylamide 이각각 1기관에서오답을보고하였다. D-methamphetamine 의음성정도관리물질농도는 50.0 ng/ml 미만이었고양성정도관리물질농도는 1,901 ng/ml 이었다. Free morphine 과 lysergic acid diethylamide 약물역시양성및음성정도관리물질농도차이가매우크므로정성검사에서오답을보고한기관은결과보고시사무적오차가있었는지여부와남용약물검사의 cut-off 를점검할필요가있었다. 또한남용약물검사의뢰건수가적은기관에서는검사 kit 의유통기한을확인한후남용약물검사를실시해야할것으로생각되었다. 결론적으로 2013 년치료적약물농도검사신빙도조사에서참여기관수는최근 5년간유사하였고, 저농도및고농도정도관리물질검사의검사실간변이계수는 2010 2012 년보다감소하 www.jlmqa.org J Lab Med Qual Assur 2014;36:12-22 21

여전반적으로약물검사의정밀도가향상된소견을보였다. 남용약물검사참여기관수는 2012 년에비해 30% 가량증가하였다. 치료적약물농도검사는환자개개인의적정약물요법을위해필수적인검사로각검사실에서는지속적인신빙도조사사업참여를통하여검사의질을높여나가야할것으로생각되었다. 약물검사분과위원 (2013) 전사일 ( 위원장, 울산의대 ), 구금경 ( 간사, 서울아산병원 ), 권계철 ( 충남의대 ), 김병광 ( 세브란스병원 ), 김승완 ( 건국대학교병원 ), 김정호 ( 연세의대 ), 서순팔 ( 전남의대 ), 송경은 ( 경북의대 ), 송정한 ( 서울의대 ), 윤여민 ( 건국의대 ), 이수연 ( 성균관의대 ), 이용화 ( 순천향의대 ), 정태동 ( 울산의대 ), 홍수지 ( 서울대학교병원 ) REFERECES 1. Kim JQ, Jung YS, Kwon OH, Kwon HJ, Kim YK, Kim JW, et al. Annual report on 2008 external quality assessment in therapeutic drug monitoring in Korea (1995). J Clin Pathol Qual Control 2009;18:119-25. 2. Kim JH, Lee W, Kim BK, Lee SY, Chun S, Kwon GC, et al. Annual report on 2008 external quality assessment in therapeutic drug monitoring and drug of abuse in Korea (2008). J Lab Med Qual Assur 2009;31:125-41. 3. Kim JH, Kim BK, Lee W, Lee SY, Chun S, Kwon GC, et al. Annual report 2010 external quality assessment in therapeutic drug monitoring and drug of abuse in Korea. J Lab Med Qual Assur 2011;33:S115-30. 4. Kim JH, Kim BK, Kim KW, Lee SY, Kwon GC, Chun S, et al. Annual report 2011 external quality assessment in therapeutic drug monitoring and drug of abuse in Korea. J Lab Med Qual Assur 2012;34:S129-47. 치료적약물농도검사및남용약물검사신빙도조사결과보고 (2013) 정태동 1 구금경 1 전사일 1 김정호 2 대한임상검사정도관리협회약물검사분과위원회 1 울산대학교의과대학서울아산병원진단검사의학과, 2 연세대학교의과대학세브란스병원진단검사의학과 대한임상검사정도관리협회약물검사분과에서는 2013 년총 2 회에걸쳐치료적약물농도검사및남용약물검사의신빙도조사사업을시행하였다. 1 회차및 2 회차모두두가지농도의치료적약물농도검사정도관리물질그리고양성및음성의남용약물검사정도관리물질을대상기관에발송하여평가하였다. 치료약물농도검사신빙도조사에참여한기관은 1 차 106 기관이었다. 기관당약물농도검사종목수는평균 5.6 종목이었다. 가장많은기관에서회신한약물농도검사종목은 valproic acid 로그다음은 digoxin, phenytoin, carbamazepine, tacrolimus (FK506) 순이었다. 저농도와고농도정도관리물질의검사실간변이계수는각각 9.3%, 6.7% 였다. 검사장비는 Architect i System (Abbott Diagnostics, USA) 을가장많이사용하였고, Cobas Integra (Roche Diagnostics, Switzerland), Cobas c501 (Roche Diagnostics) 순이었다. 남용약물검사신빙도조사참여기관은 2012 년보다약 30% 증가하였고, 정답률은 1 회차때에는 100.0% 였고, 2 회차때에는 98.2% 였다. 2013 년도약물검사분과위원회신빙도조사사업결과치료적약물농도검사의정밀도가향상되었다. 약물검사를실시하는각검사실에서는지속적인신빙도조사사업참여를통해검사의질을높여나가야할것으로생각되었다. (J Lab Med Qual Assur 2014;36:12-22) 교신저자 : 전사일우 )138-736 서울시송파구올림픽로 43 길 88, 울산대학교의과대학서울아산병원진단검사의학과 Tel: 02)3010-4513 Fax: 02)478-0884 E-mail: sailchun@amc.seoul.kr 22 J Lab Med Qual Assur 2014;36:12-22 www.jlmqa.org