한국임상약학회지제 28 권제 1 호 Korean J Clin Pharm, Vol. 28, No. 1, 2018 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.2018.28.1.24 Korean journal of clinical pharmacy (Online) URL: http://www.ekjcp.org 조혈모세포이식을받은소아환자에서 cyclosporine 의집단약동학분석 조소연 1,2 강원구 3 이정 1 김재연 2 안숙희 * 4 곽혜선 * 1 1 이화여자대학교약학대학, 2 서울아산병원약제팀, 3 중앙대학교약학대학, 4 원광대학교약학대학 (2017년 12월 16일접수 2018년 1월 5일수정 2018년 1월 8일승인 ) Population Pharmacokinetics of Cyclosporine after Hematopoietic Stem Cell Transplantation in Pediatric Patients So Yeon Cho 1,2, Jeong Yee 1, Wonku Kang 3, Jae Youn Kim 2, Sook Hee An* 4, and Hye Sun Gwak* 1 1 College of pharmacy & Division of Life and Pharmaceutical Sciences, Seoul 03760, Republic of Korea 2 Department of pharmacy, Asan Medical Center, Seoul 05505, Republic of Korea 3 College of pharmacy, Chungang University, Seoul 06974, Republic of Korea 4 College of pharmacy, Wonkwang University, Iksan 54538, Republic of Korea (Received December 16, 2017 Revised January 5, 2018 Accepted January 8, 2018) ABSTRACT Background: Cyclosporine is an immunosuppressive agent used to treat and prevent graft versus host reaction (GVHR) a complication associated with stem cell transplantation. This study aimed to develop a population pharmacokinetic model of cyclosporine and investigate factors affecting cyclosporine clearance in pediatric hematopoietic stem cell transplant patients. Methods: A total of 650 cyclosporine concentrations recorded in 65 patients who underwent hematopoietic stem cell transplantation were used. Data including age, sex, weight, height, body surface area (BSA), type of disease, chemotherapy before stem cell transplantation, type of donor, serum creatinine levels, total bilirubin concentration, hematocrit value, and type of concomitant antifungal agents and methylprednisolone used were retrospectively collected. Data related to cyclosporine dosage, administration time, and blood concentration were also collected. All data were analyzed using the non-linear mixed effect model; a twocompartment model with first-order elimination was used. Results: The population pharmacokinetic model of cyclosporine using the NONMEM program was as follows: CL (L/h) = 5.9 (BSA / 1.2) 0.9, V2 (L) = 54.5, Q (L/h) = 3.5, V3 (L) = 1080.0, k a (h -1 ) = 0.000377. BSA was selected as a covariate of cyclosporine clearance, which increased with an increase in BSA. Conclusion: A population pharmacokinetic model for Korean pediatric hematopoietic stem cell transplant patients was developed, and the important factor affecting cyclosporine clearance was found to be BSA. The model might contribute to the development of the most appropriate dosing regimen for cyclosporine. Further studies on population pharmacokinetics should be carried out, prospectively targeting pediatric patients. KEY WORDS: Cyclosporine, stem cell transplantation, population pharmacokinetics, pediatrics 조혈모세포이식은현재흔히알려져있는백혈병또는재생불량성빈혈과같은양성또는악성혈액질환, 면역학적질환을앓고있는소아환자의치료법으로사용된다. 1) 조혈모세포이식은항암화학요법또는방사선요법으로암세포와환자의조혈모세포를제거하고타인의조혈모세포를이식해주는 치료법으로, 질환을앓고있는소아환자의생존율을증가시키고있다. 그러나이식시발생하는합병증또한적지않으며, 생길수있는합병증으로는급성혹은만성이식편대숙주반응, 간정맥폐쇄질환, 출혈성방광염, 이차성악성종양, 패혈증등이있고이중에서도이식편대숙주반응의경우는발생빈도가 *Correspondence to: Hye Sun Gwak, College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 05505, Republic of Korea Tel: +82-2-3277-4376, Fax: +82-2-3277-2851 E-mail: hsgwak@ewha.ac.kr Sook Hee An, College of Pharmacy, Wonkwang University, 460 Iksandae-ro, Iksan-si, Jeonbuk 54538, Republic of Korea Tel: +82-63-850-6821, Fax: +82-63-850-7309 E-mail: shan7@wku.ac.kr 24
조혈모세포이식을받은소아환자에서 cyclosporine 의집단약동학분석 / 25 높다. 2-4) 이식편대숙주반응을예방하거나치료하기위해서 cyclosporine, tacrolimus, methotrexate, methylprednisolone, mycophenolate mofetil, azathioprine, antithymocyte globulin, infliximab 등의약물이사용되고있으며그중에서 cyclosporine은가장일반적으로쓰이고있는약물이다. 5) Cyclosporine은지용성이큰약물로생체이용률은음식, 담즙및기타상호작용요인에의해영향을받는다. 소아는성인보다장의길이가짧고장에서의흡수가제한되어있어경구투여시더많은용량을필요로한다. 간이나신장의기능이저하되어있는환자의경우에는신기능과간기능을모니터링하면서용량을조절해야하는것으로알려져있다. Cyclosporine은 cytochrome P450에의해서간에서대사되며이로인해서각개체마다편차가나타날수있다. Cyclosporine 의분포는물리화학적특성뿐만아니라지질단백이나적혈구와같은생물학적운반체의영향을받는다. 6) 위와같은이유로 cyclosporine은개체간에서뿐만아니라개체내에서도편차가나타나는약동학적특성이있다. 이전의연구에따르면대체적으로소아에서성인보다 cyclosporine의청소율이높게나타나는경향을보인다. 7) 그리고조혈모세포이식을받은환자는조혈모세포이식전받은고용량항암요법이나방사선치료또는위장관이식편대숙주반응등에의해서위장관감염이일어나기쉽고이로인한위장관변화로인해서 cyclosporine의흡수는고형장기이식을받은환자보다낮은것으로알려져있다. 8) Cyclosporine은치료영역이좁을뿐만아니라위에서처럼약동학적특성이각개체마다다르게나타나고이식의종류, 나이, 병용약물에따라서도다르게나타나므로 therapeutic drug monitoring (TDM) 을통해약물의용량을조절하여약물의치료효과를유지하도록하고있다. 9,10) Cyclosporine의약동학에관한연구는주로신장이나간과같은고형장기이식을중심으로이루어졌으며, 조혈모세포이식의경우에는성인을대상으로한연구가대부분으로조혈모세포이식을받은소아환자를대상으로한집단약동학연구는부족한실정이다. 11-15) 따라서본연구에서는조혈모세포이식을받은소아환자에서 cyclosporine의집단약동학분석을통해서소아의 cyclosporine 의약동학적특성을알아보고이에영향을미치는인자들을알아보고자하였다. 연구방법 연구대상및연구기간 2008년 1월부터 2010년 9월까지서울A병원에서조혈모세포이식을받고이식편대숙주반응의예방및치료요법으로 cyclosporine을투여받은소아병동입원환자를대상으로하였다. 환자는동종조혈모세포이식또는제대혈조혈모세포이식을받았다. 자료수집및연구방법 자료수집항목전자의무기록을통해후향적으로환자에대한자료를수집하고분석하였다. 기초정보인대상환자의나이, 성별, 몸무게, 키, 체표면적을조사하였다. 그리고질병의종류, 이식전사용한화학요법의종류, 공여자와의관계, 이식후일수를기록하였다. Cyclosporine이투여되는기간동안환자의혈청크레아티닌 (serum creatinine), 총빌리루빈 (total bilirubin), 헤마토크리트 (hematocrit), 병용투여된항진균제의종류, methylprednisolone 의병용여부를관찰, 기록하였다. 또한투여된 cyclosporine의용량과투여속도, 약물의혈중농도와채혈시간, 투여방법도기록하였다. Cyclosporine의투여및혈중농도분석 Cyclosporine은주사또는경구로 12시간간격으로투여되었다. 약물은처음 1.5 mg/kg/dose 주사로 2시간동안주입되었으며치료영역 (100-300 ng/ml) 을유지하도록의료진의판단하에용량이조절되었다. 환자의상태가경구투여가가능한시점에서주사에서경구로투여방법이전환되었다. 채혈은다음약물이투여되기 30분전에이루어졌으며 cyclosporine의혈중농도는 immunoassay법으로측정되었다. Cyclosporine의반감기를고려하여같은용량으로투여된 60 시간이후의항정상태의 cyclosporine의혈중농도만수집하였다. 약동학분석방법분석은 NONMEM (version 5.1.1; GloboMax LLC, Hanover, MD, USA) 프로그램을사용하였다. First order method를사용하였으며 two compartment model을가정하여 ADVAN4, TRANS4를이용하였다. 수집된 cyclosporine의혈중농도를통해서추정된약동학적파라미터는 clearance (CL), volume of the central compartment (V2), inter-compartmental clearance (Q), volume of the peripheral compartment (V3), absorption rate (K a ) 이었다. 기초모델 (base model) 은다른공변수없이낮은 objective function value (OBFV) 를찾는과정을통해결정하였다. Inter-individual variability는 proportional model을사용하여구하였다. OBFV를비교하여기초모델을결정하고공변수를차례대로적용하여기초모델에서부터시작하여 forward selection을통해서가장크게 OBFV의차이를나타내는최종모델 (final model) 을구하였다. OBFV의차이가 3.84 이상을나타낼때유의성 (P=0.05, 자유도 1) 이있는것으로판단하였다. 적용된공변수는키, 몸무게, 체표면적, 성별, 나이, 공여자와의관계, 혈청크레아티닌, 총빌리루빈, 헤마토크리트, 병용투여된항진균제의종류, methylprednisolone의투여여부였다. 키, 몸무게, 체표면적, 나이, 혈청크레아티닌, 총빌
26 / Korean J Clin Pharm, Vol. 28, No. 1, 2018 리루빈, 헤마토크리트는연속변수로성별, 공여자와의관계, 병용투여된항진균제의종류, methylprednisolone의투여여부는이산변수로분류되었다. 통계분석수집된자료를토대로 SPSS version 12.0K for windows (SPSS Inc., 2006) 를이용하여통계분석하였고 p-value가 0.05 미만일때를통계적유의성이있다고평가하였다. 연구결과 2008 년 1 월부터 2010 년 9 월까지서울 A 병원에서조혈모세포 Table 1. Characteristics of study patients Characteristics Number (%) or Mean±S.D. (Range) Gender Male 42 (64.6%) Female 23 (35.4%) Body weight (kg) 38.9±22.0 (8.5-108.0) Height (cm) 136.6±32.5 (69.5-180.6) BSA (m 2 ) 1.2±0.5 (0.4-2.3) Age (years) 10.5±5.7 (1-22) PSCT (days) 3.9±7.4 (-1-38) SCr (mg/dl) 0.4±0.2 (0.1-0.9) TBIL (mg/dl) 0.9±0.4 (0.0-4.0) Hct (%) 28.5±4.2 (15.7-38.8) Number of blood samples 650 CSA blood concentration (ng/ml) 186.0±69.4 (47-471) Disease ALL 18 (27.7%) AML 23 (35.4%) SAA 12 (18.5%) MDS 5 (7.7%) JMML 1 (1.5%) fanconi anemia 2 (3.1%) PRCA 1 (1.5%) HLH 2 (3.1%) SCID 1 (1.5%) Transplant type Related stem cell transplantation 28 (43.1%) Unrelated stem cell transplantation 33 (50.8%) Cord blood stem cell transplantation 4 (6.1%) Conditioning regimens BuCy (busulfan+ cyclophosphamide) 15 (23.1%) BuCyATG (busulfan+ cyclophosphamide+ 3 (4.6%) Characteristics Number (%) or Mean ±S.D. (Range) BuCyPML (busulfan+ cyclophosphamide+ melphalan) 1 (1.5%) BuFluATG (busulfan+ fludarabine+ 8 (12.3%) BuFluCy (busulfan+ fludarabine+ cyclophosphamide) 8 (12.3%) BuFluCyATG (busulfan+ fludarabine+ cyclophosphamide+ 1 (1.5%) BuVPCy (busulfan+ etoposide+ cyclophosphamide) FluCyATG (fludarabine+ cyclophosphamide+ FluCyTBI (fludarabine+ cyclophosphamide+total body irradiation) 1 (1.5%) 12 (18.5%) 2 (3.1%) FluCy (fludarabine+cyclophosphamide) 3 (4.6%) CyTBI (cyclophosphamide+total body irradiation) 11 (17.0%) BSA: body surface area, PSCT: post stem cell transplantation, SCr: serum creatinine, TBIL: total bilirubin, Hct: hematocrit, ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, SAA: severe aplastic anemia, MDS: myelo dysplastic syndrome, JMML: juvenile myelomonocytic leukemia, PRCA: pure red cell anemia, HLH: haemophagocytic lymphohistiocytosis, SCID: severe combined immunodeficiency disorder 이식을받고이식편대숙주반응의예방및치료요법으로 cyclosporine 을투여받은소아환자는총 65 명이며남자는 42 명, 여자는 23명이었다. 수집된 cyclosporine의혈중농도의수는 650개였으며혈중농도의평균은 186.0±69.4(47-471) ng/ml 이었다. 질병의종류는급성골수성백혈병 (acute myeloid leukemia, AML) 이 23명, 급성림프구성백혈병 (acute lymphoblastic leukemia, ALL) 이 18명으로대부분을차지했으며다음으로는악성재생불량성빈혈 (severe apalstic anemia), 골수이형성증후군 (myelodysplastic leukemia, MDS), 연소성골수단구성백혈병 (juvenile myelomonocytic leukemia, JMML), 판코니빈혈 (fanconi anemia), 순수적혈구무형성증 (pure red cell anemia, PRCA), 혈구탐식성조직구증식증 (haemophagocytic lymphohistiocytosis, HLH), 중증복합면역결핍증 (severe combined immunodeficiency disorder, SCID) 순이었다 (Table 1). 이식을받기전사용한화학요법은 Table 1과같으며가장많이시행한화학요법은 BuCy(busulfan+cyclophosphamide) 였다. 공여자와의관계에서형제간동종조혈모세포이식을받은환자는 28명이었고타인동종조혈모세포이식을받은환자는 33명이었다. 그외에제대혈이식을받은환자는 4명이었다. 몸무게와키의평균은각각 38.9±22.0(8.5-108.0) kg, 136.6±32.5(69.5-180.6) cm이었으며체표면적의평균은 1.2±0.5(0.4-2.3) m 2 이고나
조혈모세포이식을받은소아환자에서 cyclosporine 의집단약동학분석 / 27 Table 2. Significant covariates screening MODEL OBFV OBFV BASE CL=TVCL*(1 + ETA(1)) 6761.3 - Covariate Height TVCL=θ(1)*(height/136.6)**θ(6) 6311.9-449.4 Body weight TVCL=θ(1)*(body weight/38.9)**θ(6) 6293.7-467.6 BSA TVCL=θ(1)*(BSA/1.2)**θ(6) 6290.3-471.0 Age TVCL=θ(1)*(age/10.5)**θ(6) 6323.5-437.8 BSA: body surface area OBFV: objective function value 이는평균 10.5±5.7(1-22) 세였다. 혈청크레아티닌과총빌리루빈의평균은 0.4±2.0(0.1-0.9) mg/dl와 0.9±0.4(0-4) mg/dl로나타났다. 헤마토크리트는평균 28.5±4.2(15.7-38.8)% 였다. 병용투여된항진균제의종류는 micafungin, itraconazole, voriconazole, fluconazole, amphotericin B, caspofungin, liposomal amphotericin B, voriconazole+micafungin이었다. 이중에서 cyclosporine의혈중농도에영향을주는항진균제로알려진 itraconazole 투여환자는 12명, voriconazole은 4명, fluconazole은 18명, voriconazole+micafungin은 1명이었다. Methylprednisolone은이식후이식편대숙주반응이발생하였을때치료용량으로투여되었는데이때투여받은환자는 31 명이었다. 집단약동학분석결과 NONMEM 프로그램을사용하여 cyclosporine의 two compartment model을구하였다. 기초모델의 OBFV는 6761.3 이며기초모델에서구한 population mean과 SEM (standard error of the mean, %) 의 θ값은각각 CL (L/h)=7.9(30.7%), V2 (L)=42.9(63.4%), Q (L/h)=5.3 (58.1%), V3 (L)=1200.0(40.8%), K a (h -1 )=0.000347(47.6%) 이었다 (Table 2, 3). 그리고 inter-individual variance of CL의 mean과 SEM 값은 0.39(24.6%) 이며 residual variance의 mean과 SEM는 0.16(17.5%) 이었다. 기초모델을토대로최종모델을구하기위해서조사한키, 몸무게, 체표면적, 성별, 나이, 공여자와의관계, 혈청크레아티닌, 총빌리루빈, 헤마토크리트, 병용투여된항진균제의종류, methylprednisolone을검토하였으며그중에서의미있는공변수는키, 몸무게, 체표면적, 나이였다 (Table 2). 키를적용한모델의 OBFV와기초모델의 OBFV와의차이는 6311.9, 449.4이며몸무게는 6293.7, 467.6, 나이는 6323.5, 437.8이고마지막으로체표면적은 6290.3, 471.0로가장큰 OBFV의차이를나타내었다. 가장큰 OBFV의차이를나타낸체표면적을넣은모델에나이에관한공변수를추가하였으나 OBFV값은 6290.6 로 6290.3 인체표면적만넣은모델보다조금더커졌다. 그리하여최종적으로평균 1.2 인체표면적만이식에포함되었 Table 3. Pharamacokinetic parameter estimation with the basic and final models Parameter Model Symbol Mean 으며식은다음과같았다. CL=θ(1)*(BSA/1.2)**θ(6) 최종모델에서구한 population mean 값과 SEM (standard error of the mean, %) 의 θ값은각각 CL (L/h)=5.9(14.4%), V2 (L)=54.5(31.0%), Q (L/h)=3.5(31.2%), V3 (L)=1080.0(5.5%), K a (h -1 )=0.000377(27.9%) 이었다 (Table 3). 그리고 CL의 interindividual variance mean과 SEM값은 0.06(30.7%) 이며 residual variance는 0.11(12.2%) 로기초모델의값보다감소하였다. θ(6) 의 mean 과 SEM 는 0.9(11.2%) 이다. CL 의 inter-individual variability 는기초모델 39.0% 에서 6.2% 로감소하였다. 최종모델에서구한 observed concentrations (DV)(ng/mL) 에대한 population medel-predicted concentration (PRED)(ng/mL) 의산포도, observed concentrations (DV)(ng/mL) 에대한 individual model-predicted concentrations (IPRED)(ng/mL) 의산포도는 Figure 1에나타내었다. 고찰및결론 SEM (%) Inter-individual variability (%) CL (L/h) basic θ1 7.9 30.7 39 final 5.9 14.4 6.2 θ6 0.9 11.2 V2 (L) basic θ2 42.9 63.4 final 54.5 31 Q (L/h) basic θ3 5.3 58.1 final 3.5 31.2 V3 (L) basic θ4 1200.0 40.8 final 1080.0 5.5 K a (h -1 ) basic θ5 0.000347 47.6 final 0.000377 27.9 Inter-individual basic 0.39 24.6 variance of CL final 0.06 30.7 Residual variance basic 0.16 17.5 final 0.11 12.2 CL: clearance, V2: volume of the central compartment, Q: inter-compartmental clearance V3: volume of the peripheral compartment, K a : absorption rate constant SEM: standard error of the mean 조혈모세포이식을받은한국소아환자를대상으로실시한 cyclosporine 의집단약동학연구에서기본모델구축단계에
28 / Korean J Clin Pharm, Vol. 28, No. 1, 2018 Fig. 1. (A) Scatter plots of population model-predicted concentrations (PRED) (ng/ml) versus observed concentrations (DV) (ng/ml), (B) Scatter plots of individual model-predicted concentrations (IPRED) (ng/ml) versus observed concentrations (DV) (ng/ml). 서구한 K a (h -1 ) 는 0.000347로문헌에나와있는흡수속도상수보다작았다. 16) 이는본연구에서얻어진농도값이최저혈중농도 (trough level) 이므로정확한흡수속도상수를도출하기어렵기때문으로해석되었다. 본연구에서는체표면적이조혈모세포이식을받은소아환자에서 cyclosporine의 clearance에유의성있게영향을주었다. 체표면적, 몸무게, 키등의공변수를적용한모델에서가장의미있게나온것은체표면적이었으며환자의체표면적이커질수록 clearance가증가하였다. OBFV값을비교해볼때몸무게, 키또한체표면적보다는적지만 clearance에영향을주며이는몸무게, 키가체표면적과관련이있다는점을고려해볼수있다. 나이도어느정도 clearance에영향을주는것으로생각이되며이또한소아가성장하면서체표면적이증가하므로관련이있는것으로생각되었다. 성인조혈모세포이식환자의경우체표면적이나나이는 cyclosporine의 clearance에영향을 미치지않는데성인환자에서는환자마다체표면적이큰차이가나지않기때문으로생각된다. 그리고성장의측면에서볼때나이는성인에서큰관련이없는것으로사료된다. 17) 본연구에서혈청크레아티닌은 clearance에큰영향을미치지않은것으로보인다. 성인신장이식환자에서는이식후일수및신기능이 clearance 감소에영향을주는것으로보고되었으나조혈모세포이식환자의경우신기능이이식전후로큰차이가나타나지않기때문에 clearance에큰영향을주지않은것으로추정해볼수있다. 17) 총빌리루빈또한소아환자의 clearance에영향을미치지않는것으로나타났다. 성인조혈모세포이식환자를대상으로한또다른연구에서는헤마토크리트가감소할수록그리고성별이남자일때 clearance가증가한다고보고하였으나이연구에서는헤마토크리트와성별의영향은나타나지않았다. 18) 조사하였던질병의종류나공여자와의관계는 clearance에영향을주지않은것으로생각된다. 급성골수성백혈병과급성림프구성백혈병이대부분을차지했으나그외의질병의종류가다양하였고환자의수가작아서공여자와의관계가영향을주지않은것으로생각할수있다. 병용약물로항진균제와 methylprednisolone을조사하였으나두요인모두 clearance에유의한영향을주지않았다. 성인간이식환자를대상으로한연구에서 prednisolone의용량이 clearance를증가시킨다는보고가있었는데이는 prednisolone이경쟁적으로약물의대사에관련된간효소를억제시키거나유도시키기때문으로설명하였다. 13) 그러나성인간이식환자를대상으로했다는점과소아조혈모세포이식환자의간기능이성인간이식환자와다르다는점을고려할때소아조혈모세포이식환자에서는 methylprednisolone이 clearance에주는영향이적은것으로추측할수있다. 항진균제는약물에따라차이는있으나 azole계항진균제같은경우는 cyclosporine의 clearance 를감소시켜 cyclosporine의농도를증가시키는것으로보고되었다. 그러나이연구에서는병용된항진균제의종류가다양하고각항진균제를대상으로한환자의수가부족하여 cyclosporine의 clearance에통계적으로유의성있는영향을주지는않는것으로나타났다. 본연구는후향적연구이며, 소아를대상으로하였기때문에포함된환자의수가적다는한계점이있지만, 조혈모세포이식을받은한국인소아환자를대상으로한집단약동학연구라는점에서의의가있다. 본연구결과를바탕으로앞으로전향적인연구가이루어져야할것으로생각된다. 또한약물상호작용과관련하여항진균제나 methylprednisolone 뿐만아니라 cyclosporine의 clearance에영향을주는것으로알려진 amlodipine, felodipine, phenytoin, carbamazepine, acyclovir 등의약물과의연구도진행된다면임상적으로더유용할정보가될것으로사료된다.
조혈모세포이식을받은소아환자에서 cyclosporine 의집단약동학분석 / 29 Cyclosporine은조혈모세포이식을받은소아환자에서이식편대숙주반응을예방및치료하는데가장보편적으로쓰이는약물이다. 그러므로약용량을결정, 조절하고그효과를예측하는것은조혈모세포이식의성공률에중요한역할을한다고할수있다. 본연구에서는조혈모세포이식을받은소아환자에서체표면적이커질수록 cyclosporine의 clearance가증가하는경향을보였으며약용량을결정할때고려해야할부분으로생각된다. 참고문헌 1. Horwitz ME. Stem-cell transplantation for inherited immunodeficiency disorders. Pediatr Clin North Am 2000;47(6):171-87. 2. Patzer L, Kentouche K, Ringelmann F, Misselwitz J. Renal function following hematological stem cell transplantation in childhood. Pediatr Nephrol 2003;18(7):623-35. 3. Baird K, Cooke K, Schultx KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin North Am 2010;57(1):297-322. 4. Cheuk DK, Wang P, Lee TL, et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 2007;40(10):935-44. 5. Jacobsohn DA. Acute graft-versus-host disease in children. Bone Marrow Transplant 2008;41(2):215-21. 6. Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 1993;24(6):472-95. 7. Del Mar Fernandez De Gatta M. Immunosuppressive therapy for pediatric transplant patients: Pharmacokinetic considerations. Clin Pharmacokinet 2002;41(2):115-35. 8. Dupuis LL, Taylor T, Saunders EF. Disposition of two oral formulation of cyclosporine in pediatric patients receiving hematopoietic stem cell transplants. Pharmacotherapy 2006;26(1):15-22. 9. Oellerich M, Armstrong VW, Kahan B, et al. Lake Louise consensus conference on cyclosporine monitoring in organ transplantation: report of the consensus panel. Ther Drug Monit 1995;17(6):642-54. 10. Belitsky P, Dunn S, Johnston A, Levy G. Impact of absorption profiling on efficacy and safety of cyclosporine therapy in transplant recipients. Clin Pharmacokinet 2000;39(2):117-25. 11. Pal Falck. A population pharmacokinetic model of cyclosporin applicable for assisting dose management of kidney transplant recipients. Clin pharmacokinet 2009;48(9):615-23. 12. Rousseau A, Leger F, Le Meur Y, et al. Population pharmacokinetic modeling of oral cyclosporin using NONMEM. Ther Drug Moni 2004;26(1):23-30. 13. Sun B, Li XY, Gao JW, et al. Population pharmacokinetic study of cyclosporine based on NONMEM in Chinese liver transplantation recipients. Ther Drug monit 2010;32(6):715-22. 14. Fanta S, Jonsson S, Backman JT, Karlsson M.O, Hoppu K. Developmental pharmacokinetics of ciclosporin-a population pharmacokinetic study in paediatric renal transplant candidates. Br J Clin Pharmacol 2007;64(6):772-84. 15. Irtan S, Saint-Marcoux F, Rousseau A, et al. Population pharmacokinetics and bayesian estimator of cyclosporine in pediatric renal transplant patients. Ther Drug Monit 2007;29:96-102. 16. Willemze AJ, Cremers SC, Schoemaker RC, et al. Ciclosporin kinetics in children after stem cell transplantation. Br J Clin Pharmacol 2008;66(4):539-45. 17. Jacobson PA, Ng J, Green KG, et al. Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation. Bio Blood Marrow Transplantation 2003;9(5): 304-11. 18. Kim SH, Kim KI, Yun HY, et al. Population pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation in leukemic patients. Korean J Clin Pharm 2010;20(1):9-16.