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1 병원약사회지 (010), 제 7 권제 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 7, No., 110 ~ 118 (010) 회원학술보고 골수이식환자에서 Azole계항진균제와의병용으로인한 Cyclosporine의혈중농도변화 서울아산병원약제팀, 이화여자대학교약학대학 a Changes in blood concentrations of cyclosporine after combination with azoles in bone marrow transplant recipients Jee-hye Jeong, Seong-gil Ryu, Jae-youn Kim, Hye-Sun Gwaka and Young-cheon Song Department of Pharmacy, Asan Medical Center 388-1, Pungnab-dong, Sonpa-gu, Seoul, , Korea a College of Pharmacy, Ewha Womans University 11-1, Daehyun-dong, Seodaemun-gu, Seoul, , Korea Abstract : Many studies of azole antifungal agents report that itraconazole is a more potent inhibitor of cytochrome P450 3A4(CYP3A4) than fluconazole. However, only a few reports from various clinical studies support it. This study was performed to study the effect of itraconazole and fluconazole on metabolism of cyclosporine(csa), substrate of CYP3A4, by analyzing the blood concentrations of CsA. Total 141 patients who underwent bone marrow transplantation and were administered itraconazole or fluconazole combined with CsA from January 008 to June 009 in Asan Medical Center were enrolled. Data was collected retrospectively from electronic medical record(emr). 56 patients received 389.9mg/day itraconazole(sporanox solution, Janssen Korea) and 85 patients received 18.4mg/day fluconazole(diflucan cpasule, Pfizer Korea). The dosage of CsA was not significantly different between itraconazole group(intravenous CsA.95± 0.1mg/kg/day; oral CsA 3.59±1.51mg/kg/day) and fluconazole group(.90±0.33mg/kg/day, p=0.351; 3.88±1.54mg/kg/day, p=0.466). Also, the period of combination was about 19 days in both groups. The blood concentrations of CsA were analyzed after combination with azoles. Data was collected three times; the first level(pre-steady-state level), the third level(steady-state level) and the highest level(peak TDM level) during the period of combination. In itraconazole group, blood concentrations of CsA were ±59.91, ±68.03 and ±143.75ng/ml, respectively and peak TDM level was higher than the therapeutic range of CsA(100~300ng/ml). In fluconazole group, blood concentrations of CsA were 96.85±45.80(p=0.615), ±60.75 (p=0.051) and 7.35±18.88ng/ml(p=0.006), respectively and peak TDM level was significantly

2 정지혜 : 골수이식환자에서 Azole 계항진균제와의병용으로인한 Cyclosporine 의혈중농도변화 lower than in itraconazole group. In conclusion, more careful monitoring of blood concentrations of CsA is recommended when CsA is combined with itraconazole than when combined with fluconazole. [Key words] cyclosporine, itraconazole, fluconazole, drug-drug interaction 투고일자 ; 심사완료일자 ; 게재확정일자 연구배경및목적 Fluconazole 은 candida 감염에사용하는항진균 제로골수이식환자들에게진균감염예방목적으로사용되고있다. Itraconazole은 candida 감염외에도 aspergillus 감염에도사용할수있어 fluconazole과같이골수이식환자들에게진균감염예방목적으로사용되고있다. 1-4) 이러한 fluconzole, itraconzole과같은 azole계항진균제는약물대사에작용하는효소인 cytochrome P450(CYP450) 와다양한분자들의세포막통과에관여하는 p-glycoprotein transport system을억제하여다양한약물들과상호작용을나타낸다. 5) 상호작용을나타내는약물에는 HMG-CoA reductase inhibitors, benzodiazepines, phenytoin, carbamazepine, cyclosporine, tacrolimus, sirolimus, methylprednisolone 등이있다. 1) 이중에서도 cyclosporine은면역억제제로서골수이식환자에서사용이불가피하기때문에진균감염목적으로사용되는 azole계항진균제와병용투여될가능성이높다. 이전의연구들에서, 실제임상에서 azole계항진균제는다양한약물들과잠재적인상호작용가능성을갖는것으로나타났고그중상당수는 cyclosporine과의상호작용인것으로분석되었다. 6-7) 또, 여러종류의 azole계항진균제는약물상호작용을일으킬때각각그강도의차이를보이는데, 다양한문헌및연구결과에의하면 itraconazole이 fluconazole에비해높은강도를갖는다고한다. 1,5,8) 하지만, 실제임상에서이를뒷받침할만한연구 보고는많지않다. 따라서, 본연구에서는골수이식을받은환자에서 cyclosporine(csa) 을투여하면서 azole계항진균제인 itraconazole과 fluconazole을경구복용했을시, CsA의혈중농도변화를분석하여두약물이각각체내에서 CsA의혈중농도에미치는영향을비교하고자하였다. 연구방법 1. 대상환자 008년 1월에서 009년 6월까지해당기간에서울아산병원에서골수이식을받고입원치료를받은환자들중에서 CsA과 fluconazole 또는 itraconazole을함께처방받은환자 31명을대상으로연구하였다. 이들중약물동태학적특성이다른 14세미만의소아, CsA와 fluconazole 또는 itraconazole 을함께처방받기는했지만실제로병용된적이없는환자, fluconazole 또는 itraconazole이경구투여가아닌정맥주사된환자, itraconazole을캡슐로복용한환자를연구에서제외시켜 1명의환자를대상으로연구를진행하였다.. 연구방법후향적, 관찰적, 추적연구로, 전자의무기록을통해환자에대한자료를수집하고분석하였다. 위의대상환자들에대하여성별, 연령, 키, 체중, 진단명, 골수이식을받기전에사용한화학요법의종류등기초정

3 JKSHP, VOL.7, NO. (010) 보를조사하였다. 그리고 CsA과 azole계항진균제의병용시작일및종료일, 병용기간동안각각의제형, 병용시작일의약물용량 (mg/day), 병용종료일의약물용량 (mg/day) 등약물사용정보에대해서도조사하였다. CsA의혈중농도는세가지조건에대해서분석되었다. CsA의혈중농도가 steady-state에도달하기이전의 level로서 CsA 투여시작후첫번째혈중농도 (1 st TDM level), steady-state로가정되는세번째혈중농도 (3 rd TDM level), 병용시작일부터병용종료후 7일 5,9) 후까지의기간동안가장높았던혈중농도 (Peak TDM level) 를분석하였다. 원내에서는 CsA 투여시작다음날첫번째혈중농도를확인하고이후지속적으로일주일에 3회채혈하여 CsA의혈중농도를모니터링하고있다. 따라서, 세번째혈중농도는 CsA 투여시작일로부터약일주일째에해당하는 level로 steady-state의 level로가정될수있다. CsA의혈중농도는 RIA(radioimmunoassay) method로 trough level에대해측정되었다. 또, CsA의높은혈중농도로인한부작용발생여부를확인하기위해 peak TDM level을나타냈던날짜의간기능지표 (AST, ALT, ALP, total bilirubin, direct bilirubin) 및신기능지표 (serum creatinine, GFR) 의수치에대해서조사하였고, CsA 의혈중농도를높일수있는약물 (Table 1.) 의병용투여여부에대해서도조사하였다. 9) Table 1. CsA의혈중농도를높일수있는약물 * Significance Rating Amiodarone Androgens Azole antifungal agents β-blockers Calcium channel blockers Echinocandins Macrolide antibiotics Serotonin reuptake inhibitors danazole methyltestosterone fluconazole ketoconazole itraconazole voriconazole carvedilol nicardipine verapamil diltiazem caspofungin micafungin azithromycin erythromycin clarithromycin fluoxetine paroxetine fluvoxamine sertraline * Drug Interaction Facts 008 Lippincott Williams & Wilkins 3. 통계수집된자료는 SPSS version 1.0K for Windows (SPSS Inc., 006) 를이용하여통계분석하였고 p- value가 0.05 미만일때를통계적유의성이있다고평가하였다. 연구결과 1. 환자기초정보 을각각의건수로다루었다. 그래서 itraconazole을투여한환자는총 56명, fluconazole을투여한환자는총 85명으로두군의특성은 table. 와같다. 평균연령, 실제체중, 성별등에대해서두군간의유의한차이는나타나지않았으며, 가장많은진단명은급성골수성백혈병이었다. 골수이식을받기전에가장많이시행한화학요법은 BuFluATG로 busulfan, fludarabine, antithymocyteglobulin(atg) 를사용하였다. 대상환자는총 1 명으로이들중 19 명은 itraconazole 과 fluconazole 을모두투여받았고이들

4 정지혜 : 골수이식환자에서 Azole 계항진균제와의병용으로인한 Cyclosporine 의혈중농도변화 Table. Clinical characteristics of patients(n=141) Age, years Median(range) ABW*, kg Mean±SD(range) Gender, n(%) Male Female Diagnosis, n(%) AA* ALL* AML* CML* Lymphoma MDS* Others* Conditioning, n(%) BuCy* BuCyATG* BuFlu* BuFluATG* BuFluCampath* CyATG* CyFluATG* FluMel* FluMelATG* Itraconazole(n=56) 4(16-70) 6.9±10.00(4.7-84) 30(53.6) 4(49.4) 5(8.9) 11(19.6) 17(30.4) (3.6) 4(7.1) 14(5.0) 3(5.4) 4(7.1) 1(1.8) 7(1.5) 35(6.5) 1(1.8) (3.6) (3.6) 1(1.8) 3(5.4) Fluconazole(n=85) 43(18-70) 63.79±11.87(4.5-10) 4(49.4) 43(50.6) 6(7.1) 18(1.) 38(44.7) 0(0) 4(7.1) 17(0) (.4) 10(11.8) 1(1.) 11(1.9) 49(57.6) 1(1.) (.4) 4(4.7) 3(3.5) 4(4.7) *ABW, actual body weight; AA, aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; Others, acute biphenotypic leukemia, haemophagocytic lymphohistiocytosis and PNH; BuCy, busulfan+cyclophosphamide; BuCyATG, busulfan+cyclophosphamide+atg(antithymocyteglobulin); BuFlu, busulfan+fludarabine; BuFluATG, busulfan+fludarabine+atg; BuFluCampath, busulfan+fludarabine+alemtuzumab; CyATG, cyclophosphamide+atg; CyFluATG, cyclophosphamide+fludarabine+atg; FluMel, fludarabine+melphalan; FluMelATG, fludarabine+melphalan+atg

5 JKSHP, VOL.7, NO. (010) Table 3. 투여된대상약물의병용기간, 제형및용량 Itraconazole 투여군 (n=56) Fluconazole 투여군 (n=85) P/value 병용일수 (day) 19. (±19.7) 18.7 (±1.1) CsA 의혈중농도최고치가나타날때까지의일수 (day) 1.7 (±7.0) 1.9 (±9.3) 정맥주사용 CsA 용량, mg/day (±31.07) (±36.904) 0.95 체중당정맥주사용 CsA 용량, mg/kg/day.95 (±0.1).90 (±0.33) 경구투여용 CsA 용량, mg/day 5.93(±105.95) (±10.04) 체중당경구투여용 CsA 용량, mg/kg/day 3.59 (±1.51) 3.88 (±1.54) Azole 계항진균제투여용량, mg/day (±41.5) 18.4 (±50.7) * 평균 (± 표준편차 ). 투여된약물정보 CsA와 azole계항진균제는골수이식환자들에서약 19일동안병용되었으며, 병용시작후 CsA의혈중농도최고치가나타날때까지평균약 13일이걸리는것으로나타났다. Itraconazole 투여군은스포라녹스액 ( 한국얀센 ) 으로서평균 389.9mg/day의 itraconazole을복용하였고, fluconazole 투여군은디푸루칸캅셀 ( 한국화이자 ) 로서평균 18.4mg/day의 fluconazole을복용하였다. CsA은제형에따라투여된용량의차이를보였는데, itraconazole 투여군에서정맥주사용 CsA은.95±0.1mg/kg/day, 경구투여용 CsA은 3.59 ±1.51mg/kg/day의용량으로투여되었고 fluconazole 투여군에서는각각.90± 0.33mg/kg/day(p=0.351), 3.88± 1.54mg/kg/day(p=0.466) 의용량으로투여되어, 투여된 CsA 용량에대해두군간에유의한차이를보이지않았다. (Table 3.) 3. CsA의혈중농도변화 CsA과 fluconazole 또는 itraconazole을병용하는기간동안 CsA의혈중농도변화를살펴보았다. CsA의혈중농도는 ng/ml를참고영역으로 하여평가하였다. CsA 투여시작후첫번째혈중농도 (1 st TDM level), steady-state로가정되는세번째혈중농도 (3 rd TDM level), 병용시작부터병용종료후 7일까지의기간내에서가장높았던혈중농도 (peak TDM level) 에대해분석한결과는 Fig. 1과같다. CsA 투여시작후첫번째혈중농도 (1 st TDM level) 는 itraconazole군에서평균 ± 59.91ng/ml, fluconazole군에서 96.85± 45.80ng/ml로유의한차이를나타내지않았으나 (p=0.615), steady-state로가정되는세번째혈중농도 (3 rd TDM level) 부터는 itraconazole군평균 ±68.03ng/ml로 fluconazole군 (173.74± 60.75ng/ml, p=0.051) 에비해높은값을보이기시작하여 peak TDM level은 itraconazole군에서 ± ng/ml로 CsA의치료영역 (100~300ng/ml) 을벗어나면서 fluconazole군 (7.35±18.88ng/ml, p=0.006) 에비해통계적으로유의하게높은값으로나타났다. 각군에서 peak TDM level을나타냈을때의 CsA 제형에따른혈중농도를비교해보았는데, 그결과 CsA이경구투여용일때가정맥주사용일때보다높은혈중농도를나타내는것으로분석되었다. Itraconazole군에서 peak TDM level의평균은 CsA이정맥주사용일때 300.5±18.15ng/ml, 경구투여용일때 405.5±147.ng/ml(p=0.010) 로 CsA의제형이경구투여용일때유의하게높은혈중

따라서, 타약물이결과에영향을줄수있는가능성을배제시키기위해 Table 1에해당하는약물의병용투여여부에대해조사하였다.

6 정지혜 : 골수이식환자에서 Azole 계항진균제와의병용으로인한 Cyclosporine 의혈중농도변화 Fig. 1 병용한 Azole 계항진균제의종류에따른 CsA 혈중농도비교 Fig. CsA의제형에따른 CsA 혈중농도비교 (Peak TDM level) 농도를보였다. Fluconazole군에서도마찬가지로 CsA이정맥주사용일때와경구투여용일때의 peak TDM level 평균이각각 7.56±91.94ng/ml, ±147.39ng/ml(p<0.001) 로경구투여용일때높은혈중농도를보였다. (Fig. ) 위의결과들은모든대상환자들에대해분석한결과로 CsA의혈중농도를높일수있는다른약물의병용투여여부가고려되지않았다. 따라서, 타약물이결과에영향을줄수있는가능성을배제시키기위해 Table 1에해당하는약물의병용투여여부에대해조사하였다. Table 1에정리된약물은 Drug Interaction Facts 라는 3차문헌에서해당기준에따라약물상호작용의정도를분류한 significance rating 1, 에해당하는것으로, 본연구에서는 voriconazole, nicardipine, diltiazem, micafungin이총 1명에서병용되었다. voriconazole 은 itraconazole군 명, fluconazole군 1명, nicardipine은 itraconazole군 5명, fluconazole 군 명, diltiazem은 fluconazole군 1명, micafungin은 fluconazole군 1명에서병용투여되었다. 이들의경우위약물들에의해 CsA의혈중농도가높아졌을가능성을배제시킬수없기때문에이들을제외시킨후 CsA의혈중농도를재비교해보았다. 그결과는 Fig. 3과같고, 이는이전의결과 (Fig. 1) 와유사한경향을보였다

7 JKSHP, VOL.7, NO. (010) Fig. 3 CsA 혈중농도를높이는타약물이병용투여된경우를제외시킨후비교 을때신독성과간독성을나타내는지에대해알아보고자했다. CsA과 azole계항진균제의병용기간중가장높았던혈중농도를나타냈던날의간기능지표및신기능지표의수치를분석한결과, CsA의혈중농도와지표들간의상관관계는없는것으로나타났다. (Fig. 4) 고찰및결론 Fig. 4 Peak TDM level과 GFR(glomerular fitration rate) 의상관관계 4. CsA 의혈중농도와간기능, 신기능변화와의관계 CsA 은가장흔한독성으로신독성, 신경독성을나타내고그외에도피부, 간, 소화기, 혈액학적독성을나타낸다. 이에본연구에서는 CsA 이 azole계항진균제와의상호작용으로높은혈중농도를나타내었 골수이식후 CsA 은이식편대숙주질환의예방및 치료목적으로투여된다. 이때 CsA의혈중농도가높으면 CsA 의독성이증가하고, 혈중농도가낮으면이식편대숙주질환및이식거부반응이일어날수있으므로 CsA 의혈중농도를적절히유지하는것이중요하다. 10-1) 하지만, CsA은사람마다흡수율의차이를보이고위장관운동성, 투여형태, 약물-약물, 약물-음식상호작용등의영향을받아다양한약물동력학적성질을갖기때문에혈중농도를적절히유지하기위해서는주기적으로 CsA 의혈중농도를확인하고용량을조절하는것이필요하다. 13) 본연구에서

8 정지혜 : 골수이식환자에서 Azole 계항진균제와의병용으로인한 Cyclosporine 의혈중농도변화 는골수이식환자에서 azole계항진균제와 CsA의상호작용으로인한 CsA의혈중농도변화에대해분석했다. CsA이투여되고 itraconazole이병용된경우혈중농도최고치는첫 CsA 혈중농도에비해 4.3배증가하였고, fluconazole이병용된경우는 3.배 (p=0.010) 증가하였다. 이와같이 itraconazole을투여한경우에통계적으로유의하게더높은혈중농도증가율을보였으므로, 본연구는 itraconazole이약물상호작용에있어서 fluconazole에비해높은강도를갖는다는문헌및다양한연구결과 1,5,8) 를임상적으로뒷받침하는결과를나타내었다고할수있다. 또, CsA의제형이경구투여용일때가정맥주사용일때보다높은 CsA 혈중농도를나타낸연구결과는상호작용을나타내는두대상약물이경구투여용일때상호작용의효과가더크다는것을의미한다고할수있다. 이는간효소인 CYP450에의해대사받는약물이정맥주사로투여되는경우간을거치지않아초회통과효과를받지않지만, 경구투여되는경우위장관으로흡수되고장간순환을하면서 CYP450에의한간대사의영향을더많이받게되기때문이다. 또한, p-glycoprotein transport system은간, 신장, 소장, 대장등에높은수준으로분포하므로경구투여제형이정맥주사제형에비해 p-glycoprotein transport system에의한약물상호작용의영향을크게받기때문이기도하다. 5) 결론적으로골수이식환자에서 CsA과 oral solution itraconazole을병용하는경우 fluconazole capsule을병용할경우보다더주의깊게 CsA의혈중농도변화를모니터링할것을추천한다. 특히, 병용하는기간중에 CsA을정맥주사용에서경구투여용으로전환하게될경우, 더주의해야한다. 그러나, 본연구는 oral solution 제형의 itraconzaole 과 capsule 제형의 fluconazole을복용한환자들을대상으로진행되었으므로두 azole계항진균제의제형차이에따른생체이용율의영향을배제할수없었다. 향후 CsA와 azole계항진균제의병용시임상에서최적의효과를나타내기위한치료지침에대한연구가필요하다. 참고문헌 1) George R.Thompson III, Jose Cadena, and Thomas F. Patterson: Overview of antifungal agents, Clin Chest Med, 30, 03-15(009) ) Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, Leitz GJ, and Territo MC.: Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial, Ann Intern Med,138, (003) 3) Kieren A. Marr, Fulvio Crippa, Wendy Leisenring, Maggie Hoyle, Michael Boeckh, S. Arunmozhi Balajee, W. Garrett Nichols, Benjamin Musher, and Lawrence Corey: Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants, Blood,103, (004) 4) Yoshikazu Ito, Kazuma Ohyashiki, Isao Yoshida, Makoto Takeuchi, Yasutaka Aoyama, Atsuko Mugitani, Yasuhiro Matsuura, Hisashi Wakita, Mitsuhiro Matsuda, Erina Sakamoto, Toru Kiguchi, Akio Urabe, Kazuo Tamura, Akihisa Kanamaru, Toru Masaoka and The Japan Febrile Neutropenia Study Group: The prophylactic effect of itraconazole capsules and fluconazole capsules for systemic fungal infections in patients with acute myeloid leukemia and myelodysplastic syndromes: a Japanese multicenter randomized, controlled study, Int J Hematol,85,11-17 (007) 5) Aline H. Saad, Daryl D. DePestel, and Peggy L. Carver: Factors influencing the

9 JKSHP, VOL.7, NO. (010) magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants, Pharmacotherapy, 6(1), (006) 6) Fanny Depont, Fre de ric Vargas, Herve Dutronc, Emmanuelle Giauque, Jean- Marie Ragnaud, Tatiana Galpe rine, Abdelilah Abouelfath, Ruddy Valentino, Michel Dupon, Guillaume He bert and Nicholas Moore: Drug-drug interactions with systemic antifungals in clinical practice, Pharmacoepidemiol Drug Saf, 16, (007) 7) Yu DT, Peterson JF, and Seger DL: Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions, Pharmacoepidemiol Drug Saf, 14, (005) 8) Back D. J. and Tjia J. F.: Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes, Br. J. clin. Pharmac, 3, (1991) 9) David S.Tatro: Drug Interaction Facts 008, Wolters Kluwer Health, St. Louis, (008) 10) Simpson D: Drug therapy for acute graft-versus-host disease prophylaxis, J Hematother Stem Cell Res, 9, (000) 11) Arai S and Vogelsang GB: Management of graft-versus-host disease, Blood Rev, 14, (000) 1) Yee GC., Self SG., McGuire TR., Carlin J., Sanders JE., Deeg HJ. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation, N Eng J Med, 319, (1988) 13) Michael E.,Winter:Basic Clinical Pharmacokinetics, 4th edition, Lippincott Williams & Wilkins, Baltimore, 8-50 (004)

황지웅

황지웅 Comparison of Laparoscopy and Exploration in the Distal Pancreatectomy BACKGROUND: To determine the benefits of laparoscopic surgery compared with exploration, the clinical outcomes of open and laparoscopic