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한국임상약학회지제 29 권제 2 호 Korean J Clin Pharm, Vol. 29, No. 2, 2019 Original Article Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy pissn 1226-6051 eissn 2508-786X https://doi.org/10.24304/kjcp.2019.29.2.89 Korean journal of clinical pharmacy (Online) URL: http://www.ekjcp.org 침습성아스페르길루스증의치료목적으로 voriconazole 을단독으로투여받는폐이식환자에서 voriconazole 약물혈중농도모니터링의유효성검증 손유정 1 이경아 1 조주희 1 김재송 1 손은선 1 * 박무석 2 * 1 연세대학교의과대학세브란스병원약무국, 2 연세대학교의과대학내과학교실 (2019 년 2 월 22 일접수 2019 년 4 월 30 일수정 2019 년 5 월 7 일승인 ) Validation of Voriconazole Therapeutic Drug Monitoring in Lung Transplant Recipients Receiving Voriconazole alone for Treatment of Invasive Aspergillosis Yu Jeong Son 1, Kyung A Lee 1, Ju Hee Jo 1, Jae Song Kim 1, Eun Sun Son 1 *, and Moo Suk Park 2 * 1 Department of Pharmacy, Severance Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea 2 Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (Received February 22, 2019 Revised April 30, 2019 Accepted May 7, 2019) ABSTRACT Background: Invasive aspergillosis (IA) is associated with high morbidity and mortality, particularly among immunocompromised patients, such as lung transplant recipients. Voriconazole, the first-line therapy for IA, shows a non-linear pharmacokinetic profile and has a narrow therapeutic range. Careful and appropriate administration is necessary, primarily because it is used for critically ill patients; however, the clinical usefulness of therapeutic drug monitoring (TDM) has not been sufficiently verified. Therefore, in this study, we validated the safety and efficacy of voriconazole TDM in lung transplant recipients receiving only voriconazole for IA treatment. Methods: The electronic medical records of lung transplant recipients ( 19 years of age) administered only voriconazole for > 7 days for treatment of IA from June 1, 2013 to May 31, 2018 were analyzed retrospectively. Results: Among the 54 patients, 27 each were allocated to TDM and non-tdm groups, respectively. There were no significant differences in patient characteristics between the two groups except for ICU-hospitalization status. Of the TDM group patients, 81.5% needed adjustment of voriconazole dosage because the levels were out of target range. Comparison of two groups showed that treatment response was higher throughout treatment and switching rates of second-line agents were significantly lower in the TDM group, but it was insufficient to confirm safety improvements through voriconazole TDM. Conclusions: Considering that the treatment response tended to be higher and the rates of switching to second-line antifungal agents were lower in the TDM group, voriconazole TDM may increase the therapeutic effect on IA in lung transplant patients. KEY WORDS: Voriconazole, invasive aspergillosis, lung transplantation, therapeutic drug monitoring 침습성진균감염 (invasive fungal infections, IFIs) 은주로면역기능이저하된환자에서발생하는기회감염증으로, 항암요법이나조혈모세포이식을받는환자와면역억제제, 스테로이드를사용하는환자, 인간면역결핍바이러스 (human immunodeficiency virus, HIV) 감염등면역결핍증환자에게주로발생하며최근그발생빈도가증가하고있다. 1) 그중침습성아스페르길루스증 (invasive aspergillosis) 은면역저하환자에서생명을위협하는주요질환으로치료실패율이절반에이르고, *Correspondence to: Eun Sun Son, Department of Pharmacy, Severance Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea Tel: +82-2-2228-6888, Fax: +82-2-2227-7983 E-mail: sespharm@yuhs.ac Moo Suk Park, Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea Tel: +82-2-2228-1940, Fax: +82-2-393-6884 E-mail: PMS70@yuhs.ac 89

90 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 진단후 12주이내에사망할확률이 30% 에이를정도로치명적이다. 2) 특히고형장기이식중폐이식을받은환자에게서침습성아스페르길루스증의발현율은 15-35% 이며사망률은약 60% 에육박한다. 3-6) Voriconazole은미국감염질환학회 (Infectious Diseases Society of America, IDSA) 가이드라인및유럽임상미생물학감염학회 (European Society of Clinical Microbiology and Infectious Diseases, ESCMID) 가이드라인에서권고되는침습성아스페르길루스증의 1차치료제로, 7,8) 2002년 amphotericin B deoxycholate와비교하는대규모임상시험에서 voriconazole군이더우월하다는치료결과를입증한이후모든치료지침과교과서에서 1차치료제로인정받고있다. 9) Triazole 계열의 voriconazole은진균의 lansterol 14-αdemethylase를방해하여세포막내의 ergosterol 합성을억제하여항진균효과를나타낸다. 10) 2006년국내에도입된이후사용량의증가와함께전체항진균제중차지하는비율이매년증가하고있다. 11) 그러나 voriconazole은비선형적약동학을보일뿐아니라, 연령, 병용약제, CYP2C19 유전형에따라대사율차이가크게나타난다. 10,12) 심지어동일환자에서동일용량을투여함에도 voriconazole의혈중농도가넓게분포되는 intraindividual variability를보여투여용량과혈중약물농도간관계가예측불가능하다는특징을가지고있다. 10,12,13) 또한 voriconazole은좁은치료역 (therapeutic range) 을가지는약물로, 최근 voriconazole의혈중약물농도는침습성아스페르길루스증에대한 voriconazole의임상적효과및부작용과상관관계가있다고보고되고있다. 4,14-17) Voriconazole의약동학을기반으로한메타분석연구에의하면, voriconazole의혈중농도가 1.0 mg/l 이하일경우치료효과가현저히떨어지며, 혈중농도가 1.5 mg/l 이상일경우 IFIs가치료될확률이 85% 이지만, 4.5 mg/l 이상일경우 15% 에서신경독성이발생한다고보고된바있다. 18,19) 이러한 voriconazole의약동학, 약력학적특징과함께면역저하환자등중증질환자들에게주로사용되고있음을고려하면신중하고적절한투여가필요하지만침습성아스페르길루스증에취약한폐이식환자에서 voriconazole 치료약물농도모니터링 (therapeutic drug monitoring, TDM) 의임상적유용성에대해서는연구가부족한실정이다. 폐이식환자의 IFIs 예방목적으로 voriconazole 을투여한 Mitsani D. 등의연구에서는주기적인 TDM을통해 voriconazole 용량조절을시행하였으며, 그결과폐이식환자에서 voriconazole 혈중농도와 IFIs 예방효과의상관성을입증하였다. 또한 IFIs 고위험군인폐이식환자에서 voriconazole TDM의필요성을언급하였다. 하지만 Mitsani D. 등의연구는 IFIs 치료가아닌예방에국한된연구였으며, 이식후초기단기간관찰에그쳐장기적인이익에대한분석이불가능하였다. 4,19) 따라서본연구에서는침습성아스페르길 루스증의치료목적으로 voriconazole 을단독으로투여받는폐이식환자에서 voriconazole TDM의유효성과안전성을검증해보고자한다. 자료수집 연구방법 선정기준본연구는한상급종합병원에서 voriconazole TDM을본격적으로시행하기시작한 2016년도를기점으로하여전 후추적기간을고려해연구기간을 2013년 6월 1일부터 2018년 5월 31일까지로설정하였고해당연구기관에서침습성아스페르길루스증의치료를위해 voriconazole (Vfend inj 또는 Vfend tab ) 을투여받은폐이식이력 { 한국표준질병사인분류 (KCD7) 코드 Z94.2} 이있는만 19세이상의성인환자를대상으로시행하였다. 침습성아스페르길루스증은 2008년 Mycology Study Group of the European Organization for Research and Treatment of Cancer(EORTC/MSG) 기준에따라분류하였고, 의무기록상 거의틀림없는 (probable) 또는 확진된 (proven) 침습성아스페르길루스증으로평가된환자만을연구대상에포함하였다. 20) 제외기준침습성아스페르길루스증에대한 voriconazole 연속투여기간이 7일미만인환자, 21) voriconazole 외다른항진균제를 3일이상병용한환자는연구대상에서제외하였다. 단, nystatin 가글, fluconazole 가글, terbinafine 연고등과같은국소작용목적의항진균제병용은제외기준에포함시키지않았다. Voriconazole TDM 기준 Voriconazole은경구투여시 90% 이상의높은생체이용률 (bioavailability) 을나타내주사제와경구제의호환이가능하며, voriconazole의항정상태는부하용량을투여한경우 voriconazole 투여시작 3일후, 부하용량없이유지용량으로시작한경우 voriconazole 투여시작 7일후로알려져있다. 12,21) 따라서본연구에서는항정상태도달후인 voriconazole 투여시작 7일이후시행된 TDM 결과만을수집하였고 21) voriconazole 의유효혈중농도범위는해당연구기관의기준에따라 1.0-5.5 mg/l로정의하였다. 데이터수집항목 I. 환자의특성환자의기본특성을확인하기위하여나이, 성별, 신장, 체중, body mass index (BMI), 면역억제제및항생제병용정보, 중

폐이식환자에서침습성아스페르길루스증치료시 Voriconazole TDM 의유효성검증 / 91 환자실 (intensive care unit, ICU) 입실여부, voriconazole 투여중패혈성쇼크 (septic shock) 발생여부, 이전 IFIs 감염력, 2008년 EORTC/MSG 진균감염진단기준에따른진균감염분류데이터를수집하였다. 20) 또한처방의적절성을확인하기위하여 voriconazole 사용량, 투여기간, TDM 시행여부및그결과에대한자료를수집하였다. 이유로 voriconazole 투여를종료한경우, 해당환자의임상반응평가는제외하였다. 2차평가지표로써 voriconazole 치료실패로인한타항진균제로의약제전환율, 항진균제총사용기간, IFIs로인한재입원율, 3개월내사망률, 총재원기간, ICU 재원기간, ventilator 사용기간에대한자료를추가적으로수집하였다. Ⅱ. 임상반응평가임상반응평가는투여종료시점과치료시작 2주, 6주, 12주시점에시행하였으며이는 IDSA 가이드라인에서권고하는항진균제최소투여기간인 6-12주와항진균제초기반응평가시점을고려하여설정하였다. 7,17) 임상반응평가는 EORTC/MSG에서제안한치료반응의정의에근거하여임상증상 {procalcitonin 22), c-reactive protein (CRP), 백혈구 (white blood cell, WBC), 절대호중구수 (absolute neutrophil count, ANC) 수치및기침, 객담, 체온, PaO 2 /FiO 2 }, 방사선학적소견 { 컴퓨터단측촬영 (computed tomography, CT), chest X-ray}, 미생물학적소견 {Aspergillus 종에대한조직검사, 배양검사, 혈청또는기관지폐포세척액 (bronchoalveolar lavage fluid, BALF) galactomannan assay}, 생존여부를종합하여판단하였다. 23,24) 평가항목들이모두호전된경우는완전반응 (complete response, CR), 진균감염의미생물학적소견이호전되었으며그외평가항목들이부분적으로개선된경우는부분반응 (partial response, PR), 호전소견은없으나진행이멈춘상태는안정상태 (stable disease, SD), 증상이나방사선학적소견, 미생물학적소견이악화된경우는질환의진행 (progression of disease, PD) 그리고사망으로구분하였고, CR과 PR을양호한반응 (success) 으로 SD, PD 그리고사망을불량한반응 (failure) 으로분류하였다 (Table 1). 24) 각임상반응평가시점이전에 CR, 약제전환, 사망등의 III. 안전성평가안전성평가를위하여혈구수치 {WBC, ANC, 적혈구 (red blood cell, RBC), 헤모글로빈 (hemoglobin, Hb), 혈소판 (platelet, PLT)}, 간기능 {alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (T.bil)}, 신기능 {blood urea nitrogen (BUN), serum creatinine (SCr)}, 전해질 (sodium, potassium, calcium) 그리고기타 ( 부정맥여부, 심전도상 QTc 연장여부, 시각장애여부, 발진여부 ) 자료를수집하였다. 부작용평가시, 약제와해당부작용간의시간적인과성을확보하기위해 voriconazole 투여이후새롭게발생한부작용사건만을수집하였다. 또한간기능, 신기능, 전해질항목의경우, 기저상태의차이에의한 bias를감소시키기위해치료 1일차와투여기간내최고및최저수치와의차이를비교하였다. 각부작용의발생여부는해당연구기관의지침과 Common Terminology Criteria for Adverse Events ver. 5.0 (CTCAE 5.0) 에지시된수치범위를근거로하여평가하였으며그기준은 CTCAE 5.0 grade3 이상에해당하는수치로백혈구감소증은 WBC <2.0 10 3 /μl, 호중구감소증은 ANC <1.0 10 3 / μl, 빈혈은 Hb <8.0 g/dl, 혈소판감소증은 PLT <50.0 10 3 / μl로정의하였다. 해당임상자료는전자의무기록 (electronic medical record, EMR) 을이용하여후향적으로수집하였다. Table 1. General criteria for global responses to antifungal therapy Outcomes, response Treatment success Complete response Partial response Lack of response Criteria Survival within the prespecified period of all attributable symptoms and signs of disease and radiological abnormalities, and mycological evidence of eradication of disease Survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease and radiological abnormalities, and evidence of clearance of cultures or reduction of fungal burden, as assessed by a quantitative and validated laboratory marker Survival within the prespecified period of observation and minor or no improvement in fungal disease, Stable disease a but no evidence of progression, as determined on the basis of a composite of clinical, radiological, and mycological criteria Evidence of progressive fungal disease based on a composite of clinical, radiological, and Progression of fungal disease mycological criteria Death Death during the prespecified period of evaluation, regardless of attribution a In certain invasive fungal diseases(e.g., invasive mold diseases), stabilization of fungal disease during periods of severe immunocompromise provides evidence of efficacy of treatment and may be a reasonable short-term therapeutic goal until immune recovery occurs.

92 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 자료분석및통계수집한자료에대하여연속형변수와범주형변수로나누어각각통계적분석을실행하였다. 연속형변수중정규분포를따르는자료는 Independent t-test를시행하였고, 평균과표준편차로표현하였다. 연속형변수중비정규분포를따르는자료는 Mann-Whitney U test를시행하였고, 중앙값과범위로표현하였다. 범주형변수는기대빈도가 5보다작은셀이 20% 미만인경우 Chi-square test를, 20% 이상인경우 Fisher s exact test를시행하였으며절대값과백분율로나타내었다. 자료분석은 Microsoft office Excel 2016과 IBM SPSS statistics ver. 23.0 (IBM Co., Armonk, NY, USA) 을사용하였고, 유의수준은 p <0.05로정의하였다. 피험자보호본연구는국내한상급종합병원에서수행된단일기관후향적연구로, 해당병원의기관윤리위원회 (Institutional Review Board, IRB) 의승인을받아절차대로진행하였다 (IRB number: 4-2018-0915). 연구결과 환자군의특성연구기간 (2013년 6월 1일-2018년 5월 31일 ) 동안단일상급종합병원에서침습성아스페르길루스증의치료목적으로 voriconazole을경구또는정맥투여한폐이식이력이있는선 정대상환자는 67명이었으며이중 voriconazole 연속투여기간이 7일미만인 5명, 타항진균제를병용투여한 8명을제외하여, 총 54명을대상으로연구를진행하였다. 약제투여기간내 voriconazole 항정상태도달후 1회이상 voriconazole TDM을시행한환자군 (TDM 시행군 ) 은 27명, voriconazole TDM을시행하지않은환자군 (TDM 비시행군 ) 은 27명으로조사되었다 (Fig. 1). 총 54명환자의평균나이는 55.2±10.9세이고, 남성이 34명 (63.0%) 였다. Voriconazole TDM 시행여부에따라분류한환자군의특성을비교하기위해나이, 성별, 신장, 체중, BMI, 이전 IFIs 감염력, 병용약제 ( 면역억제제, 항생제 ) 에대하여통계분석을시행한결과모든항목에서두군간유의한차이를보이지않았다 (Table 2, 3). 그러나 ICU 입실비율은 TDM 시행군이 17명 (63.0%), TDM 비시행군이 9명 (33.3%) (p =0.029) 으로 TDM 시행군에서통계적으로유의하게높은비율을보였고 voriconazole 투여중세균에의한패혈성쇼크여부또한 TDM 시행군이 12명 (44.4%), TDM 비시행군이 5명 (18.5%) (p = 0.040) 으로 TDM 시행군에서유의하게높았다. 침습성아스페르길루스증은 EORTC/MSG 분류상 TDM 시행군과비시행군에서각각 proven 10명 (37.0%), 11명 (40.7%), probable 17명 (63.0%), 16명 (59.3%) 으로관찰되었다 (Table 2). Voriconazole 사용및 TDM 현황 Voriconazole 투여와관련된항목을살펴보면, 초기투여시 voriconazole의부하용량은 TDM 시행군과비시행군에서각각 9.0 ± 2.2, 9.4 ± 3.1 mg/kg/day (p =0.633) 였고, 유지용량 Fig. 1. Study flow diagram: screening and enrollment of patients. a Voriconazole TDM was performed more than once after reaching of voriconazole steady state during the voriconazole administration. TDM, therapeutic drug monitoring

폐이식환자에서침습성아스페르길루스증치료시 Voriconazole TDM 의유효성검증 / 93 Table 2. Baseline patient characteristics TDM (n = 27) non-tdm (n = 27) Total (n = 54) p-value Age, years 55.1 ± 11.1 55.3 ± 11.2 55.2 ± 10.9 0.800 a Gender Male, N(%) 16 (59.3) 18 (66.7) 34 (63.0) 0.573 b Female, N(%) 11 (40.7) 09 (33.3) 20 (37.0) Height, cm 165.3 ± 8.00 164.9 ± 7.10 165.1 ± 7.400 0.540 a Weight, kg 053.8 ± 11.5 052.3 ± 10.6 53.1 ± 10.9 0.870 a BMI, kg/m 2 19.6 ± 3.6 19.2 ± 3.6 19.4 ± 3.50 0.830 a Immunosuppressive drug Triple regimen c 21 (77.8) 19 (70.4) 40 (74.1) 0.535 b Double regimen d 002 (7.4) 04 (14.8) 06 (11.1) 0.669 b Triple regimen included basiliximab e 04 (14.8) 04 (14.8) 08 (14.8) 1.000 b ICU care, N(%) 17 (63.0) 09 (33.3) 26 (48.1) 0.029 b Septic shock, N(%) 12 (44.4) 05 (18.5) 17 (31.5) 0.040 b History of IFIs, N(%) 03 (11.1) 002 (7.4) 05 (9.2) 1.000 b Invasive fungal infection Proven, N(%) 10 (37.0) 11 (40.7) 21 (38.9) 0.780 b Probable, N(%) 17 (63.0) 16 (59.3) 33 (61.1) Data are the mean ± SD or No. (%) a From the Independent t-test b From the Chi-square test or Fisher s exact test c Triple regimen; tacrolimus, mycophenolate mofetil plus steroid d Double regimen; tacrolimus plus steroid e Triple regimen included basiliximab; basiliximab, mycophenolate mofetil plus steroid BMI, body mass index; ICU, intensive care unit Table 3. Antibiotics use between therapeutic drug monitoring (TDM) and non-tdm groups TDM (n = 27) non-tdm (n = 27) Total (n = 54) p-value Penicillins, N(%) 4 (14.8) 3 (11.1) 7 (13.0) 1.000 Pip/Tazo, N(%) 14 (51.9) 10 (37.0) 24 (44.4) 0.273 Cephalosporins, N(%) 2 nd generation 1 (3.7) 2 (7.4) 3 (5.6) 1.000 3 rd generation 19 (70.4) 14 (51.9) 33 (61.1) 0.163 4 th generation 11 (40.7) 8 (29.6) 19 (35.2) 0.393 Carbapenems, N(%) 21 (77.8) 19 (70.4) 40 (74.1) 0.535 Fluoroquinolones, N(%) 25 (92.6) 20 (74.1) 45 (83.3) 0.142 Aminoglycosides, N(%) 17 (63.0) 11 (40.7) 28 (51.9) 0.102 Macrolides, N(%) 9 (33.3) 7 (25.9) 16 (29.6) 0.551 Tetracyclines, N(%) 2 (7.4) 1 (3.7) 3 (5.6) 1.000 Glycopeptides, N(%) 21 (77.8) 18 (66.7) 39 (72.2) 0.362 Oxazolidinones, N(%) 5 (18.5) 2 (7.4) 7 (13.0) 0.420 Polymyxins, N(%) 14 (51.9) 8 (29.6) 22 (40.7) 0.097 Metronidazole, N(%) 10 (37.0) 6 (22.2) 16 (29.6) 0.233 TMP/SMX, N(%) 26 (96.3) 23 (85.2) 49 (90.7) 0.159 Data are the No. (%) From the Chi-square test or Fisher s exact test Pip/Tazo, piperacillin/tazobactam; TMP/SMX, trimethoprim/sulfamethoxazole

94 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 Table 4. Voriconazole use between therapeutic drug monitoring (TDM) and non-tdm groups Baseline TDM (n = 27) non-tdm (n = 27) Total (n = 54) p-value Loading dose, mg/kg/day 9.0 ± 2.2 9.4 ± 3.1 9.2 ± 2.7 0.633 Maintenance dose, mg/kg/day 7.7 ± 1.5 7.8 ± 1.4 7.7 ± 1.5 0.750 Duration of voriconazole use, days 164 [32-937] 69 [10-571] 120 [10-937] 0.004 Data are the mean ± SD or median [min-max] From the Independent t-test or Mann-Whitney U test 은각각 7.7 ± 1.5, 7.8 ± 1.4 mg/kg/day (p =0.750) 로두군간유의한차이를보이지않았다. 그러나 voriconazole의투여기간은 TDM 시행군에서 164[32-937] 일, TDM 비시행군에서 69[10-571] 일로 TDM 시행군에서 voriconazole의투여기간이더길었다 (p = 0.004) (Table 4). Voriconazole TDM 시행의적절성을판단하기위해 TDM 시행군에서각환자의약제투여기간내 voriconazole TDM 횟수를조사하였고평균주당 0.5 ± 0.3회시행됨을알수있었다. TDM 시행결과, 초기 voriconazole trough level은 3.1 ± 2.2 mg/l, 투여기간내평균 voriconazole trough level은 2.4 ± 1.5 mg/l로측정되어목표혈중농도인 1.0-5.5 mg/l 내로유지되었다 (Table 5). TDM 시행군 27명중약제투여기간내 Table 5. Voriconazole therapeutic drug monitoring (TDM) results in TDM group TDM (n = 27) Number of voriconazole TDM a, N/week 0.5 ± 0.3 Initial voriconazole trough level, mg/l 3.1 ± 2.2 Average of voriconazole trough level, mg/l 2.4 ± 1.5 Data are the mean ± SD a TDM results which were performed after reaching of voriconazole steady state (7 days after starting voriconazole administration) were included voriconazole 목표혈중농도를 1회이상이탈한환자는 22명으로, TDM 시행군중 81.5% 에해당하는환자가 TDM 결과에따른용량조절이필요한것으로나타났다. 그러나, 이중 68.2% 에해당하는 15명만실제용량조절이시행되었고나머지 7명 (31.8%) 은용량조절없이투여가지속되었다 (Fig. 2). 치료효과 EORTC/MSG 기준에의거하여 TDM 시행여부에따른치료반응을투여시점별로분석한결과 TDM 시행군과비시행군의양호한반응의비율은각각투여 2주시점 (40.7% vs. 22.2%; p =0.143), 6주시점 (44.0% vs. 36.8%; p = 0.632), 12 주시점 (47.8% vs. 30.8%; p = 0.319), 투여종료시점 (48.1% vs. 40.7%; p =0.584) 으로나타나모든시점에서통계적으로유의한차이를보이지는않았으나 TDM 시행군에서모두양호한반응의비율이높은경향을보였다 (Fig. 3). 2차평가지표를 TDM 시행여부에따라분석한결과, TDM 시행군과비시행군에서 IFIs로인한재입원율 (37.0% vs. 48.1%; p = 0.410), 3개월사망률 (7.4% vs. 14.8%; p = 0.390), ICU 재원기간 (7[0-149] 일 vs. 0[0-163] 일 ; p = 0.288), ventilator 사용기간 (4[0-177] 일 vs. 0[0-152] 일 ; p =0.236) 에서통계적으로유의한차이를보이지않았다. 그러나, voriconazole 치료실패로인한 2차항진균제로의약제전환은 TDM 시행군에 Fig. 2. Voriconazole therapeutic drug monitoring (TDM) results and the application ratio in TDM group. Data are No. (%). a TDM results performed after reaching of voriconazole steady state(7 days after starting voriconazole administration) were included. b Voriconazole trough levels < 1.0 mg/l or > 5.5 mg/l

폐이식환자에서침습성아스페르길루스증치료시 Voriconazole TDM 의유효성검증 / 95 Fig. 3. Treatment responses in therapeutic drug monitoring (TDM) vs. non-tdm groups at 2, 6, 12 weeks, and the end of voriconazole administration. Data are No. (%). From the Chi-square test or Fisher s exact test. a Patients who completed voriconazole within 6 weeks were excluded from the analysis; 2 patients in TDM group, 8 patients in non-tdm group. b Patients who completed voriconazole within 12 weeks were excluded from the analysis; 4 patients in TDM group, 14 patients in non-tdm group 비해 TDM 비시행군에서더높은전환율을보이며통계적으로유의한차이를보였다 (25.9% vs. 55.6%; p = 0.027) (Table 6). 2차항진균제의경우, TDM 시행군과비시행군모두에서 liposomal amphotericin B로의전환이가장빈번하였고그종류및비율은두군간유의한차이가없었다 (Table 7). 반면 TDM 시행군과비시행군에서항진균제총사용기간 (166[32-937] 일 vs. 93[16-734] 일 ; p =0.012) 과총재원기간 (66[6-473] 일 vs. 27[0-163] 일 ; p =0.049) 은통계적으로유의하게 TDM 시행군에서더길었다 (Table 6). 하지만 voriconazole 투여종료시점에서양호한반응을보인환자를대상으로 voriconazole 투여기간을추가분석한결과, TDM 시행군에서 170.9 ± 67.3일, TDM 비시행군에서 137.1 ± 97.4일로두군간유의한차이를보이지않았다 (p = 0.327) (Table 8). TDM 시행환자를대상으로 voriconazole TDM 농도가치료성공에미치는영향을알아보기위하여 TDM 시행군중투여종료시점의임상반응평가에서양호한반응을보인군 (treatment success group) 과불량한반응을보인군 (lack of response group) 의평균 voriconazole trough level을분석하였다. Voriconazole 투여기간내시행된 TDM 총횟수는양호한반응군 118회, 불량한반응군 174회였으며, 평균 voriconazole trough level은양호한반응군에서 2.6[0.4-8.0] mg/l, 불량한반응군에서 1.7[0.4-10.0] mg/l로측정되어양호한반응군에 Table 6. Comparisons of efficacy in therapeutic drug monitoring (TDM) vs. non-tdm groups TDM (n = 27) non-tdm (n = 27) Total (n = 54) p-value Switching rates to 2 nd line antifungal agents, N(%) 7 (25.9) 15 (55.6) 22 (40.7) 0.027 a Total duration of antifungal agents use, days 166 [32-937] 93 [16-734] 126 [16-937] 0.012 b Readmission to hospital for IFIs, N(%) 10 (37.0) 13 (48.1) 23 (42.6) 0.410 a 3-month mortality, N(%) 2 (7.4) 4 (14.8) 6 (11.1) 0.390 a LOS, days 66 [6-473] 27 [0-163] 59 [0-473] 0.049 b ICU LOS, days 7 [0-149] 0 [0-163] 1.5 [0-163] 0.288 b Duration of ventilator, days 4 [0-177] 0 [0-152] 2.5 [0-177] 0.236 b Data are the No. (%) or median [min-max] a From the Chi-square test b From the Mann-Whitney U test IFIs, invasive fungal infections; LOS, hospital length of stay; ICU LOS, intensive care unit length of stay

96 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 Table 7. Comparisons of 2 nd line antifungal agents in therapeutic drug monitoring (TDM) vs. non-tdm groups TDM (n = 7) non-tdm (n = 15) Total (n = 22) p-value Liposomal amphotericin B, N(%) 4 (57.1) 10 (66.7) 14 (63.6) 1.000 Caspofungin, N(%) 2 (28.6) 2 (13.3) 4 (18.2) 0.565 Combined treatment, N(%) 1 (14.3) 3 (20.0) 4 (18.2) 1.000 Data are the No. (%) From the Fisher s exact test Table 8. Duration of voriconazole use between therapeutic drug monitoring (TDM) and non-tdm groups Total Treatment success group TDM (n = 27) non-tdm (n = 27) p-value TDM (n = 13) non-tdm (n = 11) p-value Duration of voriconazole use, days 164 [32-937] 69 [10-571] 0.004 170.9 ± 67.3 137.1 ± 97.4 0.327 Data are the mean ± SD or median [min-max] From the Independent t-test or Mann-Whitney U test Fig. 4. Comparisons of median voriconazole trough levels between treatment success group and lack of response group in TDM group. Median voriconazole trough levels were significantly different between treatment success group and lack of response group among patients who received voriconazole therapeutic drug monitoring (p =0.008). Data are median [min-max]. From the Mann- Whitney U test 서통계적으로유의하게더높음을확인하였다 (p =0.008) (Fig. 4). 치료역 (1.0-5.5 mg/l) 을벗어난 voriconazole의혈중농도가치료실패에미치는영향을분석하기위하여양호한반응군과불량한반응군의 voriconazole trough level을추가분석한결과, 목표혈중농도미만측정률 (16.1% vs. 20.7%; p =0.325), 목표혈중농도초과측정률 (7.6% vs. 3.4%; p =0.112) 로두항 목모두에서두군간통계적으로유의한차이를보이지않았다 (Table 9). 안전성 Voriconazole TDM 여부에따른 TDM 시행군과비시행군의안전성을분석한결과, 백혈구감소증발생률 (25.9% vs. 22.2%; p = 0.750), 호중구감소증발생률 (3.7% vs. 14.8%;

폐이식환자에서침습성아스페르길루스증치료시 Voriconazole TDM 의유효성검증 / 97 Table 9. Comparisons of voriconazole trough level between treatment success group and lack of response group in TDM group Treatment success group (n = 118) Lack of response group (n = 174) Total (n = 292) p-value Median voriconazole trough level, mg/l 2.6 [0.4-8.0] 1.7 [0.4-10.0] 2.0 [0.4-10.0] 0.008 a Voriconazole trough level < 1.0 mg/l, N(%) 19 (16.1) 36 (20.7) 55 (18.8) 0.325 b Voriconazole trough level 5.5 mg/l, N(%) 9 (7.6) 6 (3.4) 15 (5.1) 0.112 b Data are median [min-max] or No. (%) a From the Mann-Whitney U test b From the Chi-square test Table 10. Comparisons of safety in therapeutic drug monitoring (TDM) vs. non-tdm groups TDM (n = 27) non-tdm (n = 27) Total (n = 54) p-value Cytopenia, N(%) Leukopenia 7 (25.9) 6 (22.2) 13 (24.1) 0.750 a Neutropenia 1 (3.7) 4 (14.8) 5 (9.3) 0.351 a Anemia 2 (7.4) 3 (11.1) 5 (9.3) 1.000 a Thrombocytopenia 2 (7.4) 7 (25.9) 9 (16.7) 0.142 a Liver function AST, IU/L 77.0 [11.0-2192.0] 30.0 [2.0-817.0] 60.0 [2.0-2192.0] 0.046 b ALT, IU/L 58.0 [1.0-1293.0] 26.0 [0.0-165.0] 44.0 [0.0-1293.0] 0.077 b T.bil, mg/dl 0.3 [0.0-21.3] 0.1 [0.0-21.3] 0.2 [0.0-21.3] 0.394 b Renal function BUN, mg/dl 24.7 [3.5-67.6] 14.2 [0.0-99.1] 19.4 [0.0-99.1] 0.026 b scr, g/dl 0.6 [0.0-3.6] 0.2 [0.0-3.1] 0.4 [0.0-3.6] 0.002 b Heart dysfunction, N(%) Tachycardia 3 (11.1) 4 (14.8) 7 (13.0) 1.000 a Bradycardia 0 (0.0) 0 (0.0) 0 (0.0) 1.000 a Prolonged QT interval 1 (3.7) 0 (0.0) 1 (1.9) 1.000 a Electrolyte imbalance, meq/l Serum Na increase 7.7 ± 4.4 6.1 ± 4.9 6.9 ± 4.6 0.204 b Serum Na decrease 7.7 ± 5.8 6.1 ± 5.5 6.8 ± 5.6 0.378 b Serum K increase 1.5 [0.5-4.8] 1.1 [0.0-3.3] 1.3 [0.0-4.8] 0.021 b Serum K decrease 1.0 ± 0.6 0.9 ± 0.7 1.0 ± 0.7 0.935 b Serum Ca increase 1.2 [0.0-2.8] 0.7 [0.0-2.8] 1.1 [0.0-2.8] 0.076 b Serum Ca decrease 0.9 ± 0.7 1.0 ± 1.0 0.9 ± 0.8 0.709 b Skin rash, N(%) 1 (3.7) 3 (11.1) 4 (7.4) 0.610 a Visual disturbance, N(%) 2 (7.4) 2 (7.4) 4 (7.4) 1.000 a Data are No. (%), mean ± SD or median [min-max] a From the Chi-square test or Fisher s exact test b From the Independent t-test or Mann-Whitney U test AST, aspartate aminotransferase; ALT, alanine aminotransferase; T.bil, total bilirubin; BUN, blood urea nitrogen; scr, serum creatinine p =0.351), 빈혈발생률 (7.4% vs. 11.1%; p = 1.000), 혈소판감소증발생률 (7.4% vs. 25.9%; p =0.142) 로나타나모든항목에서두군간통계적으로유의한차이를보이지않았다. TDM 시행군과비시행군의간기능분석결과, AST 증가폭 (77.0[11.0-2192.0] IU/L vs. 30.0[2.0-817.0] IU/L; p = 0.046) 은 TDM 시행군에서통계적으로유의하게높았으나, ALT 증가폭 (58.0[1.0-1293.0] IU/L vs. 26.0[0.0-165.0] IU/L; p = 0.077) 과 T.bil 증가폭 (0.3[0.0-21.3] mg/dl vs. 0.1[0.0-21.3] mg/dl; p =0.394) 은두군간유의한차이가없었다. 신기능평가를위해 BUN 증가폭 (24.7[3.5-67.6] mg/dl vs. 14.2[0.0-99.1] mg/dl; p = 0.026) 및 scr 증가폭 (0.6[0.0-3.6] g/dl vs. 0.2[0.0-3.1] g/dl; p =0.002) 을분석하였고두항목모두 TDM 시행군에서통계적으로유의하게높았다. 심기능과관련된빈맥발생여부 (11.1% vs. 14.8%; p =

98 / Korean J Clin Pharm, Vol. 29, No. 2, 2019 1.000), 서맥발생여부 (0.0% vs. 0.0%; p = 1.000), QTc 연장여부 (3.7% vs. 0.0%; p =1.000) 는두군간유의한차이를보이지않았다. 전해질불균형측면에서혈청 potassium 증가폭 (1.5[0.5-4.8] meq/l vs. 1.1 [0.0-3.3] meq/l; p =0.021) 은 TDM 시행군에서유의하게높게나타났으나, 그외다른전해질항목에서는통계적으로유의한차이가없었다. 기타안전성평가를위한발진발생여부 (3.7% vs. 11.1%; p =0.610), 시각장애발생여부 (7.4% vs. 7.4%; p =1.000) 는두군간유의한차이를보이지않았다 (Table 10). 고 폐이식환자의 5년생존율은 50% 미만으로고형장기이식환자중감염에가장취약하다고알려져있는데이는장기특성상폐는지속적으로외부환경에노출되어있고, 감기나독감등 1차감염에의해호흡기점막전체의면역력이저하되어 2차감염의위험이높아지기때문이다. 25) 특히침습성아스페르길루스증의발병률이가장높은데, 침습성아스페르길루스증은평균치사율이높아그에대한관리는매우중요하다. 5,6) 침습성아스페르길루스증의 1차치료제인 voriconazole은적응증및급여등의문제로해당연구기관에서제한항생제로분류되어감염내과에협진을의뢰하여철저한관리하에사용되고있다. 그중특히폐이식환자는주 1회 TDM을시행하여목표혈중농도 (1.0-5.5 mg/l) 를유지하도록관리하고있다. 2016 IDSA guideline과 EQUAL Aspergillosis Score 2018 guideline에서도침습성아스페르길루스증의치료를위해 voriconazole을투여할경우 TDM 시행을권고하고있다. 7,26) 그러나폐이식환자를대상으로한 voriconazole TDM 연구의경우, 약물치료효과및안전성에관한연구가지속적으로진행되고있으나예방적요법으로사용한경우에만국한되어치료효과에대한전반적인연구가부족한실정이다. 4,19) 따라서본연구는침습성아스페르길루스증에취약한폐이식환자를대상으로그임상적효과와안전성을확인하고자시행되었다. 본연구결과에따르면 TDM 시행군과비시행군의 voriconazole 투여용량은유의한차이가없었다. TDM 시행군에서 voriconazole 투여기간중 1회이상목표혈중농도를벗어난환자는 81.5% 로조사되어 voriconazole은치료역이탈률이높은약제임을확인하였다. 그중 68.2% 에해당하는환자는 TDM 결과를기반으로하여 voriconazole 용량조절을시행하였으나 31.8% 의환자는기존의투여용량을그대로유지하였다. 용량비조절의경우, 임상의의판단에따라경과관찰및 follow up TDM 시행후추후용량조절예정등의사유로사료된다. Voriconazole 투여시작후 2주, 6주, 12주, 그리고투여종료 찰 시점에서침습성아스페르길루스증에대한치료효과를분석한결과, 본연구에서는통계적으로유의한차이를보이지는않았으나, TDM 시행군에서 TDM 비시행군에비해치료효과가상승하는경향성을보였다. 또한 voriconazole 치료실패에따른 2차약제로의전환율은 TDM 시행군에서유의하게낮음을확인할수있었다 (p = 0.027). Voriconazole 투여종료사유를추가적으로분석해본결과, TDM 시행군의경우질환의호전이 27명중 13명 (48.1%) 으로가장높은비율을차지하였고, 2차약제로의전환 (6명, 22.2%) 이그뒤를이었다. TDM 비시행군은 2차약제로의전환 (15명, 55.6%), 혹은질환의호전 (11 명, 40.7%) 에의해 voriconazole 투여를종료한경우가대부분이었다. 2차약제로의전환은곧 voriconazole 치료실패를의미하므로이러한결과를통해 voriconazole 투여시 TDM을시행함으로써치료실패율이감소하였음을간접적으로확인할수있다. 간이식환자를대상으로한 Hashemizadeh 등의선행연구에서는측정된 voriconazole trough level에따른 IFIs의치료효과와 voriconazole-related 부작용의발현빈도를비교분석하였다. 선행연구에서는목표혈중농도에도달하지못한 34명의환자에서통계적으로유의하게 IFIs의치료효과가더낮았고목표혈중농도를상회한군에서 voriconazole에의한부작용발현빈도가높게나타나간이식환자에서 IFIs 치료시 voriconazole TDM을통한용량조절이필요함을확인하였다. 14) 본연구에서도 TDM을시행한환자를양호한반응군과불량한반응군으로나누어추가분석을시행한결과, 불량한반응군에서 voriconazole 목표혈중농도에도달하지못한빈도가높은경향을보였고, 반면양호한반응군에서는불량한반응군보다목표혈중농도를초과한빈도가더높은경향을보였다. 하지만통계적으로유의한값을나타내지는않았는데이는선행연구에비해본연구의대상환자수가더적었기때문인것으로사료된다. 또한양호한반응군에비해불량한반응군에서평균 voriconazole trough level이유의하게더낮았는데 (p = 0.008), 이는 voriconazole의혈중농도와치료효과의상관성을간접적으로나타낸다. 따라서 voriconazole TDM 시행은침습성아스페르길루스증의치료효과를높여궁극적으로폐이식환자의생존및예후에기여할수있을것으로보인다. 14) TDM 시행군과비시행군의환자특성을분석한결과, 환자의기저상태를반영하는 ICU 입실여부 (63.0% vs. 33.3%; p = 0.029) 가 TDM 시행군에서통계적으로유의하게높았으며 voriconazole 투여중세균감염에의한패혈성쇼크여부 (44.4% vs. 18.5%; p = 0.040) 또한 TDM 시행군에서통계적으로유의하게높았다. 이처럼 TDM 시행군에서기저상태가나빴음에도불구하고모든임상반응평가시점에서침습성아스페르길루스증에대한치료효과가 TDM 시행군이 TDM 비

폐이식환자에서침습성아스페르길루스증치료시 Voriconazole TDM 의유효성검증 / 99 시행군보다높은경향성을보였다. 또한항생제사용에따라임상증상이개선되었을가능성을배제하기위해 voriconazole 과병용투여된항생제의종류를추가분석하였으나모든계열에서두군간유의한차이를보이지않았다. 따라서본연구를바탕으로폐이식환자에서 voriconazole TDM을시행할경우, 침습성아스페르길루스증에대한치료효과를상승시킬수있을것으로사료된다. Voriconazole의투여기간을분석한결과, TDM 시행군에서 164[32-937] 일, TDM 비시행군에서 69[10-571] 일로 TDM 시행군에서더길었으나 (p = 0.004) voriconazole 투여종료시점에서양호한반응을보인환자를대상으로 TDM 시행여부에따른 voriconazole 투여기간을추가분석한결과, 두군간유의한차이가없었다 (p =0.327). 그이유를분석해보면, TDM 비시행군에서는 voriconazole 치료실패로인한 2차약제로의전환이통계적으로유의하게높았으므로 TDM 시행군에서 voriconazole 투여기간이더길었을것으로추정된다. 항진균제총투여기간도 TDM 시행군에서 166[32-937] 일, TDM 비시행군에서 93[16-734] 일로 TDM 시행군에서통계적으로유의하게더길었으며 (p = 0.012), 총재원기간또한 TDM 시행군에서 66[6-473] 일, TDM 비시행군에서 27[0-163] 일로 TDM 시행군에서통계적으로유의하게더길었다 (p = 0.049). 이는 TDM 비시행군에서 3개월내사망률 (TDM 시행군 7.4%, TDM 비시행군 14.8%; p =0.390) 이통계적으로유의하지는않았으나 TDM 시행군에비해더높은결과를보여투여기간및재원기간단축에영향을준것으로사료된다. 2012년국내에서시행된박완범등의연구에따르면, voriconazole에의해발생한부작용은 TDM 시행군과비시행군간에유의한차이가없었으나 TDM 시행군에서 voriconazole 약물부작용으로약물을중단하는환자의수가유의하게적었다 (p = 0.022). 따라서 voriconazole TDM 시행이 voriconazole에의한심각한부작용의발생을줄일수있음을보여주었다. 15) 이러한선행연구를기반으로본연구에서는 TDM 시행이폐이식환자에서 voriconazole 사용시안전성증진에기여할것이라는가정하에안전성평가를시행하였다. 하지만 TDM 시행여부에따른안전성을비교분석한결과, TDM 시행군에서 AST, BUN, scr, 혈청 potassium 증가폭이유의하게높게나타났다. 또한통계적으로유의하지는않았으나, ALT, T.bil, 혈청 sodium 및 calcium 증가폭과혈청 sodium 감소폭또한 TDM 시행군에서높은경향을보였다. 이는 TDM 자체가환자에게침습적인위해가없는절차임에도불구하고, voriconazole 투여중세균에의한패혈성쇼크발생율 (44.4% vs. 18.5%; p = 0.040) 이 TDM 시행군에서통계적으로유의하게높았던점을고려해본다면, 패혈성쇼크에의한 2차적다장기부전의발생에따른영향으로사료된다. 따라서단순히본연구결과만으로폐이식환자에서 voriconazole TDM 시행이안전성향 상에기여했다는근거를확인하기에는부족하였다. 본연구의한계점은다음과같다. 첫째, 단일기관에서진행된소규모연구로모든항목에서유의한결과를나타낼만한표본수를확보하지못하였으므로연구결과가전체의료기관의특성을반영하지못할수있다. 둘째, 후향적연구이므로검사시행의부재로대상환자의유전자다형 (CYP2C19) 에대한분석이불가능하였고, 기록미비로누락된자료가있었다. 셋째, TDM 비시행군의경우, voriconazole 혈중농도에관한정보가없었기때문에 voriconazole 혈중농도와치료효과의상관성을비교하기어려웠다. 넷째, 안전성확인측면에서 TDM 시행군과비시행군의기저상태가달라서약제에의한부작용여부를명확히확인할수없었다. 하지만이러한한계점에도불구하고본연구는폐이식환자에서 voriconazole TDM 시행여부에따른침습성아스페르길루스증치료효과와안전성을분석함으로써안전하고효과적인약물사용을뒷받침하는기초자료로서활용이가능하다는의의를지닌다. 결 본연구는폐이식환자에서 voriconazole TDM 시행여부에따른침습성아스페르길루스증치료효과및안전성을비교분석하여 voriconazole TDM의임상적유효성을확인하고, 궁극적으로약제의적절한사용과환자안전에기여하고자시행되었다. 본연구를통해 voriconazole TDM 시행군에서 81.5% 에달하는높은목표혈중농도이탈률을확인하였다. 치료효과분석결과, TDM 시행군에서 voriconazole 치료실패로인한 2차약제로의전환율이유의하게낮았고, 2주, 6주, 12주및투여종료시점에서치료반응률이높은경향을보였다. 또한투여종료시점에서양호한반응을보인환자들의평균 voriconazole trough level이불량한반응군에비해유의하게더높았다. 이는 voriconazole 혈중농도와치료효과간의상관성과함께 voriconazole TDM 시행으로치료효과가상승했을가능성을시사한다. 다만소규모후향적연구라는한계점을지니기때문에추후본연구를보완한대규모, 다기관연구가시행되어야할것이다. 론 참고문헌 1. Badiee P and Hashemizadeh Z. Opportunistic invasive fungal infections: diagnosis & clinical management. Indian J Med Res 2014;139(2):195-204. 2. Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs 2007;67(11):1567-601. 3. Gavalda J, Meije Y, Fortun J, et al. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect 2014;20 Suppl 7:27-48.

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