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1 한국임상약학회지제 20 권제 3 호 Kor. J. Clin. Pharm., Vol. 20, No 조혈모세포이식환자에서의현행 tacrolimus 치료방법평가 여미진 1 박수진 1 방준석 1 * 나현오 1,2 * 1 가톨릭대학교서울성모병원약제부, 2 가톨릭대학교의과대학약리학교실 (2010 년 9 월 30 일접수 2010 년 11 월 1 일수정 2010 년 11 월 20 일승인 ) Evaluation of the Current Regimen of Tacrolimus in Patients with Hematopoietic Stem Cell Transplantation Mi Jin Yeo 1, Soo Jin Park 1, Joon Seok Bang 1, and Hyen Oh La 1,2 1 Department of Pharmacy, Seoul St. Mary s Hospital, The Catholic University of Korea 2 Department of Pharmacology, College of Medicine, The Catholic University of Korea (Received September 30, 2010 Revised November 1, 2010 Accepted November 20, 2010) Tacrolimus, an immunosuppressant prescribed against graft-versus-host disease (GVHD) in patients with allogeneichematopoietic stem cell transplantation (HSCT), is affected to change its pharmacokinetic properties by various factors. For this reason, it is needed a close monitoring to adjust dosage amount in order to optimize the blood concentration of tacrolimus is located within the effective range. According to our in-house study, 62% of HSCT-patients were needed dosage-adjustment and it is necessary to optimize the current immunosuppressive regimen in clinical settings. A retrospective study was designed to evaluate the dosing regimen (converting ratio of IV:PO=1:4) of tacrolimus in HSCT patients (n=62). After collecting data from patient s profile and medical record, pharmacokinetic parameters were calculated and compared between the estimated and the actual values in the selected subjects (n=58). It was found that the bioavailabilty (BA) of oral tacrolimus was 40.5% very much different from that is known as 25%. It implies that the current protocol has a potent risk causes dose-related toxicities to the patients. Furthermore, analyses among factors demonstrated that there was no statistical significance between BA of tacrolimus and the variable factors. In the clinical perspectives, the current converting ratio of tacrolimus in patients with HSCT to be re-considered and an appropriate and optimal alternative regimen should be adopted to prevent GVHD and to increase the quality of life of patients. Key words - bioavailability, HSCT, GVHD, immunosuppressant, tacrolimus, TDM 이식편대숙주반응 (Graft-versus-host-disease, GVHD) 은동종조혈모세포이식 (allogeneic hematopoietic stem cell transplantation, HSCT) 을받은환자에게치료실패나사망을초래하는대표적원인으로알려져있다. HSCT 환자의약 40~50% 에서급성 GVHD가발생하므로 GVHD의예방과치료는 HSCT의성공여부에중요한역할을한다. 1,2) Tacrolimus는 cyclosporine과더불어 GVHD 발현예방에사용되는면역억제약물이며 cyclosporine 보다 HSCT 이후 Grade 2~4 수준의 GVHD 발 Correspondence to : 나현오가톨릭대학교의과대학약리학교실 서울특별시서초구반포동 505 Tel: , Fax: hola@catholic.ac.kr Correspondence to : 방준석가톨릭대학교서울성모병원약제부 서울특별시서초구반포동 505 Tel: , Fax: jsbang@catholic.ac.kr 생률을더잘감소시킨다고알려진다. 3) HSCT 환자에게 tacrolimus를투여하는통상적인 protocol 은다음과같다. HSCT 수술전날부터수술후 20일째까지 0.03 mg/kg/day씩 24시간에걸쳐 IV infusion한다. 21일째부터는투여경로를 PO로바꾸어서초기용량을 0.2 mg/kg/day 로증량하여매일 2회분할투여한다. 이어서 0.12 mg/kg/day 로감량시킨유지용량을매일 2회분할투여한다. 이와같은 protocol에따르면, IV에서 PO로투여경로를변경할때에약 25% 라고보고되어있는 tacrolimus의생체이용율 (bioavailability, BA) 값을기준으로 IV 투여용량의 4배를 PO용량으로환산하여투여한다. 4) 하지만, 본비례적방식의투여용량산출방법을임상적으로적용하였을때실제환자의혈중농도는계산으로예측된범위를자주벗어나며자체조사에따르면 HSCT 후 tacrolimus를투여받은전체환자중 62% 가임상적용량조정이필요하였다. 그러므로, HSCT 환자에투여하는 tacrolimus의경로변경시현재적용중인용량의설정방법은면역억제의치료성과는물론, 약물의과다투여로초래 193

2 194 Kor. J. Clin. Pharm., Vol. 20, No. 3, 2010 될수있는환자의안전성확보차원에서재평가의실시가요구된다. 하지만, tacrolimus는투여된용량과실제혈중농도간에는연관성이작고, 치료계수 (therapeutic index) 도작으며, 병용된약물과많은상호작용을일으키는특성을보유하였다. 1,4-8) 또한, tacrolimus 치료성과의기준으로활용되는최저혈중농도 (trough level) 값은이식한세포나조직, 장기의종류, 혈중약물농도분석방법, 이식수술방법, 병용약제의다양성, 환자개인의특징요소등에따라많은영향을받는다고알려진다. 9) 그러므로, 동일한조건하의환자뿐만아니라개별환자라도병태생리적변동상황에따라약동학적매개변수 (pharmacokinetic parameter) 의변화양상이다양하므로치료목표구간 (10~20 ng/ml) 안에항상약물의평균혈중농도값이위치하기위해서는치료적혈중약물농도모니터링 (therapeutic drug monitoring, TDM) 이필수적이다 ) 본연구는 HSCT 환자에 GVHD 예방용으로투여하는 tacrolimus의투여경로를 IV에서 PO로변경시현재적용중인 1:4 라는비례적인용량산출방법이과연환자의치료목표농도범위달성에적절한방법인지평가하기위하여실시하였다. 연구방법 연구대상자선정 2006년 1월부터총 2.5년간비혈연간 HSCT 시술후에 GVHD 발현의예방을위해 tacrolimus를투여받았던입원환자들중에서, 통상적치료 protocol에의하여 D+21 전, 후 10일동안투여경로가변경됐던전, 후의혈중농도가항정상태 (steady-state) 에도달하였고, 약물의혈중농도는물론, 혈액 화학적검사상실측 data가보존되어있는환자를연구대상으로선정하였다. 한편, tacrolimus의투여경로를전환했으나 2 주안에 steady-state에도달하지못한채퇴원했던환자 ; uncontrolled infection을가졌던환자 ; 신장기능장애 (serum creatinine 또는 blood urea nitrogen 수치가 baseline의 1.5배를초과 ) 인환자는연구대상에서제외하였다. 투여약제및혈액시료분석연구에사용된 tacrolimus는주사제 1종과경구제 2종이었고 (Prograf inj. 5 mg/ml/ampoule, Astellas Korea; Prograf 0.5, 1 mg/capsule, Astellas Korea; Tacrobell 0.25, 0.5, 1 mg/capsule, Chong Kun Dang, Korea), 모든연구대상환자는경구로약물을복용하였거나정맥으로투여받았다. 이때 IV에서 PO로투여경로변경시용량전환 ratio는 1:4를적용하였다. 혈액샘플은 HSCT후매주 2회월요일과목요일오전 8시에채혈하였고, 9,14) 약물의혈중농도는 Automated Fluorescence Polarization Analyzer (TDxFLx, Abbott, USA) 를이용하여면역형광법으로분석하였다. 15) 자료수집연구대상환자들의원내전자의무기록 (electronic medical record, EMR) 과재원시 tacrolimus의 TDM 중재를위하여작성하였던환자기록지 (patient s monitoring profiles, PMPs) 로부터필요한 data를발췌하였고, 약동학적매개변수를계산한뒤, 후향적으로분석하였다. 환자의인구통계학적 data( 등록번호, 연령, 성별, 신장, 체중, body mass index) 와병태생리학적 data( 진단명, 조혈모세포제공자와수혜자간의 ABO-type blood matching, chemotherapy regimen, IV투여와 PO변경시의 serum creatinine, total bilirubin, complete blood count, adverse Table 1. Calculation equations for pharmacokinetic parameters of tacrolimus Route Parameter Unit Equations No. of equation IV&PO IV PO IBW kg {(Height/2.54)-60}*2.3+(50 in male; 45 in female) [1] V d L 1.67 (L/kg)*IBW(kg) [2] K e_ss h -1 [{daily dose IV (mg)*1000}/24h]/{v d *C ss } [3] CL ss_iv ml/h/kg 1.67(L/kg)*K e-ss (h -1 )*1000 [4] K e_ss h -1 {F*(dose/2)*K a }/V d *(K a -K e )}*[{e -Ke*10 /(1-e -Ke*12 )} -{e -Ka*10 / (1-e -Ka*12 )}] = C ss (ng/ml) [5] CL ss_po ml/h/kg 1.67(L/kg)*K e (h -1 )*1000 [6] F - (AUC PO /dose PO )/(AUC IV /dose IV ) = CL IV /CL PO [7] IV&PO BA % F*100 [8] Abbreviations: IV (intravenous); PO (oral); IBW (ideal body weight); V d (volume of distribution); K e-ss (elimination rate constant in steady-state); C ss (blood concentration in steady-state); CL ss (creatinine clearnace in steady-state); K a (absorption rate constant); F (extent of drug absorption); AUC (area under the plasma drug concentration versus time curve); BA (bioavailability) [2] V d =1.67(L/kg)*IBW(kg) (cited from an article by Boswell GW, et al., Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant 1998; 21: 23-28); [5] K a =2.08 (cited from an article by Sam WJ, Tham LS, Holmes MJ, et al., Population Pharmacokinetics of Tacrolimus in Whole Blood and Plasma in Asian Liver Transplant Patients. Clin Pharmacokinet 2006; 45: 59-75); [5] C ss (Blood concentration of tacrolimus collected at 8:00 AM from the study patients, ng/ml); Dose (daily PO dosage*1000)

3 조혈모세포이식환자에서의현행 tacrolimus 치료방법평가 195 drug reaction, tacrolimus의투여용량과혈중농도값 ) 를획득하였다. 또한, 모든혈중농도값은 TDM을실시한후 steadystate에도달했을때의수치를사용하였다. 약동학적변수의산출및비교획득한데이터및 tacrolimus를 IV와 PO 경로로투여한때의각종약동학적매개변수를활용하여 creatinine clearance (CL) 와 bioavailability (BA) 를산출하였다 (Table 1). 그리고, IV투여후의 steady-state 혈중농도를기준으로 tacrolimus의 therapeutic range (10~20 ng/ml) 에포함되는지는산출된평균 BA값을적용해서 PO투여약물용량및혈중농도값을가지고예측하였다. 이어서, 현재적용중인용량전환 ratio (1:4) 를적용하여예측한투여용량, 혈중농도, TDM 후실제투여한용량, 혈중농도값을상호비교하였다. 16,17) 통계분석및연구윤리위원회심사획득한데이터와산출된 V d, CL, BA 값은통계처리패키지프로그램인 SAS (Ver. 9.1) 을이용하여상관관계를밝히기위하여각항목별로 t-test를실시하였고, p-value가 0.05 미만일때통계적으로유의성을가진다고인정하였다. 실험결과의비뚤림 (bias) 을감소시키기위하여모든 data의통계처리는생물통계학전문가에의뢰하여수행하였다. 또한, 본연구는기관윤리심사위원회 (Institutional Review Board) 로부터연구계획서를심사받고시행허가를획득한후진행되었으며 ( 승인번호 : SCO8RISI0136, 연구과제ID: , 승인일자 : 2008년 11월 12일 ) 연구의유효기간은승인일로부터 2 년간이었다. 연구결과 연구대상환자최초조건에부합하는환자 62명중연구포함대상의기준에미흡한환자 4명을제외하고선정된연구대상자는총 58명이었다. 실험환자는 HSCT 시술일자를기준으로 2006~2008년기간에각각 10명, 27명, 21명씩분포하였고, 성비구성은남성이 38명 (65.5%) 여성은 20명 (34.5%) 이었다. 연구대상자의평균연령은 33.4세였으며, 연령구간별분포는 11~20세 12명, 21~30세 10명, 31~40세 19명, 41~50세 13명, 51~60세 4명이었다. 진단받은질병별분포는 aplastic anemia (Severe Aplastic Anemia, Very Severe Aplastic Anemia) 12명, acute lymphoblastic leukemia (ALL) 16명, acute myeloid leukemia (AML) 21명, chronic myeloid leukemia (CML) 4명, myelodysplastic syndrome (MDS) 3 명, multiple myeloma (MM) 1명, T-cell lymphoma 1명이었다. Allo-HSCT 시술시공여자 (donor) 와수혜자 (recipient) 의 ABO식혈액형이일치한경우는 20명이었고불일치한경우는 38명이었다 (Table 2). BA와약동학적변동요인선정된연구대상자 58명의데이터로부터계산된 tacrolimus 실제평균 BA값은 40.5±14.1% 로써이제까지임상적용중인 25% 와는큰차이를보였다. 이중에서 20% 이하가 3명, 20~29% 가 12명, 30~39% 가 10명, 40~49% 가 17 명, 50~59% 가 10명, 60~69% 가 5명, 70% 이상이 1명으로나타났으며, 40~49% range에속하는환자가 29.3% 로가장많았다 (Table 3). 그리고, capsule형경구제제인 Prograf 과 Tacrobell 을복용한환자의평균 BA는각각 42.6±14.4%, 38±13.7% 로써상이한두가지제품을복용했던환자의 BA 값사이에는통계적유의성이없었다 (p=0.172) (Table 4). 다양한약동학적변화유발인자들사이의상관관계조사결과를토대로 BA PO 값예측을위한회귀모형을수립한뒤다 Table 2. Characteristics of the study subjects (n=58) Age (year) Sex ABW (kg) ABO match Disease Variable n Average BA (%) BA ranges (Min~ Max) 11~ ~ ~ ~ ~ ~ ~ ~ ~60 Mean±SD Male Female ± ~ ~ ~71.0 Mean±SD 64.2± Yes ~57.8 No ~71.0 Aplastic Anemia Acute Lymphoblastic Leukemia ~62.1 Acute Myeloid Leukemia ~71.0 Chronic Myeloid Leukemia ~57.8 Myelodysplastic Syndrome ~54.9 Multiple Myeloma Severe Aplastic Anemia ~62.7 T-cell Lymphoma Very Severe Aplastic Anemia ~51.7 Total ± ~71.0 BA (bioavailability); ABW (actual body weight)

4 196 Kor. J. Clin. Pharm., Vol. 20, No. 3, 2010 Table 3. Bioavailability of tacrolimus in the study patients (n=58) Interval ranges of bioavailability < 20 20~29 30~39 40~49 50~59 60~69 70 Patient (n) Rate (%) Table 4. Comparison of bioavailability between oral preparations of tacrolimus Oral preparation(brand name) n Bioavailability (%)* Prograf ±14.4 Tacrobell ±13.7 Total ±14.1 * Data are shown as mean±sd 중회귀분석법으로적합도를 F-test한결과는다음과같다. 환자의 tacrolimus BA값과변화유발인자들곧, 연령 (p=0.859), 신장 (p=0.147), 실측체중 (p=0.736), 이상체중 (ideal body weight, p=0.124), 체질량지수 (body mass index, p=0.218), 혈청크레아티닌 (serum creatinine, p=0.966), blood urea nitrogen (p=0.062), total bilirubin (p=0.911), AST (p=0.930), ALT (p=0.862) 사이에는어떠한상관관계의통계적유의성도없었다. 또한, BA PO 모형의검정통계량으로부터계산한확률값이 0.06이었으므로 BA PO 는통계적유의성을보일만큼각변화인자로부터영향을받지않았음을나타내었다 (Fig. 1). Tacrolimus 혈중농도 IV투여후 steady-state 혈중농도가 tacrolimus의치료범위로서최적구간 (15~17 ng/ml; Fig. 2의 y축참조 ) 에도달했던연구대상환자들의 PMP를면밀히분석하여역으로이때 IV 투여된용량값을추출하였다. 이용량값에임상적으로적용되는기지의 tacrolimus BA값 (25%) 이아닌, 각환자로부터실측된 BA값 (42.6±14.4%) 을적용함으로써유효 PO용량값을산출하였다. 이렇게산출된경구투여용량값을경구투 여후최초로 steady-state에도달한때에예측되는혈중농도값들을구하여혈중농도구간별로배치했을때 (Fig. 2의 x축참조 ) 최적치료범위 (10~20 ng/ml) 안에속하게되는환자수가실측혈중농도가 15, 16, 17 ng/ml일때, 각각 22(37.9%) 명, 22(37.9%), 35(43.1%) 명으로써다수가포함되는것으로나타났다. 이같은결과는현재임상적으로용량환산시적용하는기준 BA값이변경되어야함을입증하였다 (Fig. 2). Tacrolimus의치료적목표범위인 10~20 ng/ml 구간에혈중농도가도달하는정도를평가하기위하여첫째, 실제투여한경구용량및혈중농도를측정하였다 (Table 5, A군 ). 둘째, 현재사용중인용량전환비 (1:4), 곧 25% BA값을적용하여 PO투여용량과혈중농도구간별로할당되는환자의수를예측하였다 (Table 5, B군 ). 셋째, 연구대상환자에 IV투여후 steady-state일때실측된혈중농도값에실측된 BA값 (40%) 을적용해서 PO투여용량및이에따른혈중농도구간별로환자의수를예측해보았다 (Table 5, C군 ). 이어서 A, B, C 각군의값들이치료범위에어느정도도달하였는지비교하였다. 치료목표 IV혈중농도구간이 15~17 ng/ml가되도록 PO투여용량을환산하면, 예측한 PO혈중농도가치료목표범위에가장근접하였고, C군을기준으로 A군과 B군을비교하면모두통계적으로유의한차이가있었다. 또한, 치료농도목표간을 10~20, 5~20, 5~25, 5~15 ng/ml로세분하여 A, B, C 각군에서치료범위에도달한환자수와그비율을산출했더니 10~20 ng/ml 구간에서만통계적유의성이나타나지않았고, 나머지치료범위중에서 C군의도달비율이 77.6~91.4% 로서가장높게나타났다. 한편, IV에서 PO로투여경로를변경할때용량환산 ratio를 1:4로가정하면, 최초 steady-state에도달할때의혈중농도 (C PO_SS ) 가유효치료범위 Fig. 1. The correlations between bioavailability and body mass index, serum creatinine, total bilirubin. In each graph, Y-axis represents bioavailability (%) and X-axis demonstrates 1) BMI (kg/m 2 ), 2) Serum creatinine (ng/dl), and 3) Total bilirubin (ng/dl), respectively.

조혈모세포이식환자에서의현행 tacrolimus 치료방법평가 197 Fig. 2. Comparison of the patient numbers with estimated blood concentration range versus real concentration value. Table 5.

5 조혈모세포이식환자에서의현행 tacrolimus 치료방법평가 197 Fig. 2. Comparison of the patient numbers with estimated blood concentration range versus real concentration value. Table 5. Number of patients by tacrolimus levels with different regimens (p<0.05) Therapeutic Actual (A) Current regimen (B) New regimen (C) range (ng/ml) n % n % n % 10~ ~ ~ ~ (A): Actual (adjusted value based on the actual concentration) (B): Current regimen (BA 25%) 0.03 mg/kg IV plus 0.12 mg/kg PO (C): New regimen (BA 40%) 0.03 mg/kg IV plus mg/kg PO (10~20 ng/ml) 안에포함될비율은연구대상환자의 46.6% 에불과하였으므로이역시임상적으로적용중인현재방법이 tacrolimus의약효유지나부작용감소를위해서모두적절하지않을수도있음을보여주었다 (Table 5). 고 예전부터이론적으로정립된 tacrolimus의약동학적 compartment model은실제임상적상황에서는환자의병태생리및치료성과를정확히표현하는데미흡하다고지적되어왔다. 18,19) 그러므로, 실제임상에서는환자치료시기존약동학모델에의해계산되는예측값을활용하지않고대신 steady-state 도달후의 trough level이 therapeutic range에도달하는지를확인하면서반복적인 TDM을통하여투여용량 찰 을증감시키는경험중심의조절방법에의존한다. 20) 이에환자개인특성을고려하여약물요법을최적화, 표준화하는노력은치료학적으로큰의미를가진다. 21,22) 이번연구는조혈모세포를이식받은환자가 tacrolimus 치료중에 IV에서 PO로투여경로를변환할때흔히발생되는, 환자의혈중농도가유효범위로부터의자주이탈하는현상에대하여현재사용중인용량산출환산비의임상적적정성여부를평가한것이다. 약동학적매개변수에영향을미치는다양한변화요인을보유한 tacrolimus는변화요인들이독립적으로는큰의미가없으므로투여경로별로환자체중에비례하여투여한약물의용량과혈중에서의실제농도를측정한뒤그비율을 BA(%) 로환산하여사용하였다. 연구대상환자 58명의관련데이터를근거로 tacrolimus의실제 BA를계산하였을때평균 BA(%) 값이 40.5±14.1로서여러문헌에서제시되었거나실제 TDM 활동에적용하고있는 25% 와는많은차이가있음이밝혀졌다. 한편, tacrolimus의 BA값에영향을미치는요인들로알려진연령, 성별, 체중, 신장, 진단명, ABO-type, Scr, BUN, total bilirubin, AST, ALT 등은 BA와의관련성측면에서통계적인유의성이확인되지않았다. 더불어, 본연구에사용된상이한경구약제간평균 BA 값에도통계적유의성은없었으므로건강한한국인을대상으로두약물의약동학적매개변수를비교하였을때통계적유의성이나타나지않았다는연구결과와도일치하였다. 7) 향후에는보다임상적활용성이훨씬높은용량전환비를도출하기위해서는혈중농도가 15~17 ng/ml 구간에있었던 IV투여용량을산출하고, 그용량에 BA를 40% 로적용했을때의 PO용량을구하여새로운변환비인 1:2.5에따라 steady-state의혈중농도가 10~20 ng/ml에위치할수있는정

6 198 Kor. J. Clin. Pharm., Vol. 20, No. 3, 2010 도를전향적 (prospective) 평가하는연구가추가적으로필요하다. 본연구의한계점은다음과같다. HSCT시술후 TDM을적용했던유효한임상사례의수가많지않았으므로보다정확하고신뢰도높은결과를얻기위해서는대규모연구대상환자가필요하고장시간의추적관찰과평가가요구된다. 또한, 최근약물대사에영향을미치는유전체학적, 인구통계학적변인을고찰하는연구결과들이주목받는상황에서본연구는한국인이라는한정된표본집단을가지고진행되었다. 또한, 과거의임상치료데이터를후향적으로분석한연구가향후임상치료단계에서활용되려면실제환자에게병용투여된항암제및기타약물과의상호작용 ; tacrolimus의중간대사체에관한연구결과 ; 혈액암종, 항암제, 면역억제제와관련된약물유전체학적연구결과의융합적해석과이해가지속적으로이뤄져야하겠고 ; 투여경로변경에따른최적변환비의계산및시뮬레이션결과를전향적으로연구하여실증적으로규명함이필요하다 ) 결론적으로, HSCT후급성 GVHD 예방용도로투여하는면역억제약물 tacrolimus는그간 BA 25% 를적용하여 IV투여하다가 PO로투여경로를바꿀때용량변환비를 1:4로설정하고있는현재의치료 regimen은수정되어야하며, 환자의치료효과증대와안전성을보장하기위하여정교한약동학모델의수립은물론치료방안개선을위한추가적인연구가뒤따라야할것이다. 참고문헌 1. Hiraoka A. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogenic bone marrow transplantation. Bone Marrow Transplant 2001; 28: Ferarra JL. Advances in the clinical management of GVHD. Best Pract Res Clin Haematol 2008; 21: Fay JW, Wingard JR, Antin JH, et al., FK506 (Tacrolimus) monotherapy for prevention of Graft-Versus-Host Disease After Histocompatible Sibling Allogenic Bone Marrow Transplantation. Blood 1996; 87: Arai S, Vogelsang GB. Management of graft-versus-host disease. Blood Rev 2000; 14: Simpson D. Drug therapy for acute graft-versus-host disease prophylaxis. J Hemato Ther Stem Cell Res 2000; 9: Lesley S. Tacrolimus, A further update of its use in the management of organ transplantation. Drugs 2003; 63: Yanada M. Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan. Bone Marrow Transplant 2004; 34: Park K. A randomized, open-label, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults. Clin Ther 2007; 29: Jusko WJ, Thomson AW, Fung J, et al., Consensus document: therapeutic drug monitoring of tacrolimus (FK- 506). Ther Drug Monit 1995; 17: Staatz CE, Willis C, Taylor PJ, et al., Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin pharmacol Ther 2002; 72: Scott LJ, McKeage K, Keam SJ, et al., Taclorimus: A further update of its use in the management organ transplantation. Drugs 2003; 63: Felipe CR, Silva HT, Machado PG, et al., The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics ad therapeutic drug monitoring. Clin Transplant 2002; 16: Bekersky I, Dressler D, Alak A, et al., Comparative tacrolimus pharmacokinetics: Normal versus midly hepatically impaired subjects. J Clin Pharmacol 2001; 41: Gaston S. Maintenance immunosuppression in the renal transplant recipient. An overview. Am J Kidney Dis 2001; 38: S25-S Holt DW. Therapeutic drug monitoring of immunosuppressive drugs in kidney transplantation. Curr Opin Nephrol Hypertens 2003; 11: Jusko WJ, Piekoszewski W, Klintmalm GB, et al., Pharmacokinetics and of tacrolimus in liver transplant patients. Clin pharmacol Ther 1995; 57: Mekki Q, Lee C, Aweeka F, et al., pharmacokinetics of tacrolimus (FK506) in kidney transplant patients. Clin Pharmacol Ther 1993; 53: Rowland M, Tozer T. Clinical pharmacokinetics: Concepts and applications. 3 rd ed. Baltimore, Williams & Willkins, 1995; , Boswell GW, Bekersky I, Fay J, et al., Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant 1998; 21: Quan D, Winter ME. Immunosuppressants: Cyclosporine, tacrolimus, and sirolimus, In: Basic clinical pharmacokinetics. 4 th ed. Baltimore, MD, Lippincortt Williams & Wilkins, 2004: Cattanneo D, Perico N, RemuzzinG. From pharmacokinetics to pharmacogenomics: a new approach to tailor immunosuppressive. Am J Transplant 2004; 4:

7 조혈모세포이식환자에서의현행 tacrolimus 치료방법평가 Yagil Y, Yagil C. Pharmacogenomic considerations for immunosuppressive therapy. Pharmacogenomics 2003; 4: Weinshilboum R. Inheritance and drug response. New Eng J Med 2003; 348: Evans WE, McLeod HL. Pharmacogenomics-drug disposition, drug targets and side effects. New Eng J Med 2003; 348: MacPhee IA, Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome P4503A5 and p- glycoprotein correlate with dose requirement. Transplantation 2002; 74:

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical