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1 병원약사회지 (2018), 제 35 권제 3 호 J. Kor. Soc. Health-syst. Pharm., Vol. 35, No. 3, 292 ~ 309 (2018) Original Article Voriconazole 의용량변경현황분석및제안 이재은 a, 김승란 a, 김예지 b, 김희세 a, 김재연 a, 서울아산병원약제팀 a, 서울아산병원의학통계학과 b Analysis of Dose Changing Pattern for Voriconazole and Recommendation Jae-Eun Lee a, Seoung-Lan Kim a, Ye-Jee Kim b, Hee-Se Kim a and Jae-Youn Kim a, Department of Pharmacy, Asan Medical Center a Department of Clinical Epidemiology and Biostatistics, Asan Medical Center b 43 Olympic-ro, Songpa-gu, Seoul, 05505, Republic of Korea Background : Voriconazole is a first-line agent for treatment of invasive aspergillosis. However, the relationship between dose and serum concentration of voriconazole is non-linear, making it very difficult to predict changes in serum level of voriconazole upon dosage change. Here, we reviewed and analyzed cases of changing dose of voriconazole when its serum concentration was not within therapeutic range. Methods : We retrospectively analyzed medical records of adult patients who were hospitalized in Asan Medical Center from January 2010 to December We excluded cases whose voriconazole level was not in a steady state, those who were administered incompatible drugs, and those who were diagnosed with liver cirrhosis. The number of hospitalization was the unit of analysis. Patients were classified by their initial serum concentration of voriconazole as follows: Group 1 (G1) (TDM1; 1st level 0.5 μg /ml), G2 (0.5 TDM1 1 μg /ml), G3 (1 TDM1 5.5 μg /ml (therapeutic range)), G4 (5.5 TDM1 10 μg /ml) and G5 (TDM1 10 μg /ml). Chi-square test and Fisher s exact test were used to test if there were statistical differences between groups. This study was approved by our Institutional 투고일자 ; 심사완료일자 ; 게재확정일자 교신저자김재연 Tel: skfehs@amc.seoul.kr

2 이재은 : Voriconazole 의용량변경현황분석및제안 Review Board (No. S ). Results : A total of 574 cases were analyzed and classified into five groups. We found that 93%, 82%, 87% and 76% of G1, G2, G4 and G5, respectively, reached therapeutic range of voriconazole when their dosages were changed as follows: increased by 2 mg/kg/day, increased by 0.5 mg/kg/day, decreased by 1 mg/kg/day and decreased by 2 mg/kg/day, respectively. Conclusions : The following dose changing regimen would be more reasonable when serum level of voriconazole is not within therapeutic range: G1, increase by 2-5 mg/kg/day; G2, increase by mg/kg/day; G4, decrease by mg/kg/day; G5, skip one dose and decrease by mg/kg/day. [Key words] Voriconazole, Therapeutic Drug Monitoring, Pharmacokinetics 미국감염학회 (Infectious Diseases Society of America, IDSA) 의가이드라인에따르면보리코나졸은침습적아스페르길루스증 (invasive aspergillosis) 의 1차치료선택약이다. 1) 아스페르길루스감염은특히면역억제제를복용한환자들이나조혈모세포이식환자와같이감염에취약한환자들의사망률과이환율을높이기때문에보리코나졸을적정한용량으로복용하는것은매우중요하다. 허가받은보리코나졸의용량용법은최초 24시간동안부하용량 6 mg/kg을 12시간간격으로 1-2시간에걸쳐정맥주사한후유지용량 4 mg/kg을 12 시간마다정맥주사하거나 100 mg 또는 200 mg를 12 시간마다경구복용하는것이다. 만일경구로복용을시작할경우부하용량 400 mg로 12 시간마다복용한후 200 mg을 12시간마다복용하도록허가받았다. 2) 하지만보리코나졸의치료농도범위가좁고 (1 혈중농도 5.5 μg /ml) 환자의기저질환, 병용약물등이보리코나졸의혈중농도에영향을미쳐용량-혈중농도의상관관계가비선형적이기때문에약동학적파라미터들을구하기어려워용량변경에따른혈중농도변화예측이어렵다. 3),4) 많은연구들이특정환자군, 인종, Cytochrome P450 enzyme (CYP) 2C19, 병용약물에한정하여용량가이드를제시해왔다. 하지만여러요인들을포함한환자군을대상으로한연구는적어여전히임상현장에서는보리코나졸을투약하는동안혈중농도를측정하더 라도약물용량을변경하는데있어어려움을겪고있다. 이러한갈증을해소하고자본연구는보리코나졸의혈중농도가치료영역에서벗어났을때치료영역에도달하기위한용량변경현황을분석하고제안하고자한다. 연구방법 1. 관련문헌검색 PUBMED에서 보리코나졸의 TDM에관한연구 를주제로하고 3개의 keyword 1. Voriconazole, 2. Therapeutic drug monitoring (TDM), 3. Pharmacokinetics를이용하여이전연구논문들을검색하였다. 검색결과얻은 440개의논문중성인환자를대상으로한논문들을선택했고건강한사람만추적관찰하거나소아를대상으로한연구, in vitro 실험연구는제외했다. 또한보리코나졸의특성에관한연구 ( 약물상호작용을밝힌연구, 약물의치료농도범위설정에관한연구, TDM의필요성을확인한연구 ) 들도제외했다. 본연구와동일한연구대상자를연구한논문들을리뷰해봤을때, 다음과같은요인들 - 성별, 나이 (y), 체중 (kg), 키 (cm), 병동, 중환자실입원여부, 진료과, 진단명, 보리코나졸의투약목적, 병용약물, 신기능 (Scr; Serum creatinine, BUN; Blood Urea Nitrogen), 간기능 (AST; Aspartate aminotransferase, ALT; Alanine aminotransferase, T.BIL; Total

3 JKSHP, VOL.35, NO.3 (2018) Bilirubin, Albumin), 이식, 투석여부, 염증수치 (CRP; C-reactive Protein, WBC; White Blood Cell) - 이보리코나졸의혈중농도에영향을줄수있다고보았다. 5)-10) 2. 임상자료검색및분류 2010년 1월 1일부터 2015년 12월 31 일까지서울아산병원에입원하여보리코나졸을투여받고, 혈중농도모니터링자료가한번이상기록되어있는성인환자들중보리코나졸의혈중농도에영향을미치는요인들이없는사람들의임상자료를후향적으로분석하였다. 자료검색은환자의개인정보가삭제된자료를조회할수있는 ABLE (Asan BiomedicaL Research Environment) 프로그램을이용했다. 각내원을분석단위로하여같은환자라하더라도각내원번호마다투여량에대한혈중농도를분석하였다. ABLE 프로그램으로얻은전체내원 779건중보리코나졸의초기혈중농도가항정상태에도달하기전에측정된혈중농도만있을경우분석에서제외했다 (G0). 다음으로, 병용금기약물인리팜피신 (Rifampicin), 리파부틴 (Rifabutin), 에파비렌즈 (Efavirenz), 리토나비어 (Ritonavir), 카르바마제핀 (Carbamazepine), 바르비탈 (Barbital) 류약물을병용한환자, 병용주의약물인페니토인 (Phenytoin), 경구피임약을병용한환자를제외하였다. 병용주의약물중, 스테로이드, 수소펌프차단제 (Proton Pump Inhibitor, PPI) 약물은대부분의환자들이병용하고있어제외하지못하고분석에포함했다. 마지막으로간경화진단을받은환자는연구에서제외하였다. 간경화환자의경우보리코나졸이제거되는시간이길어지면서독성농도 (Toxic level) 로지속될가능성이높아투여용량을줄여야한다는연구는있지만, 5) Child-Pugh 점수에따른보리코나졸의제거수준이구체적으로수치화되어있는근거자료가부족하여본연구에서제외하기로하였다. 그러나과거에간경화진단을받았지만간이식을받았고, 그후에보리코나졸을투약한경우, 즉혈중농도측정날짜가간이식날짜보다늦은경우는분석대상에포함시켰다. 본연구에서는보리코나졸의혈중농도에영향을미 칠수있는요인들을알아보기위해분석할혈중농도와같은날짜에기록된다른임상자료들 - 선행연구논문들을리뷰한결과약물의혈중농도에영향을줄수있다고본성별, 나이 (y), 체중 (kg), 키 (cm), 병동, 중환자실입원여부, 진료과, 진단명, 보리코나졸의투약목적, 병용금기또는주의약물, 신기능 (Scr, BUN), 간기능 (AST, ALT, T.BIL, Albumin), 이식, 투석여부, 염증수치 (CRP, WBC) - 도함께수집하였다. 각내원번호마다분석에사용할혈중농도를선택하는방법은다음과같다. 우선보리코나졸의혈중농도가항정상태 (Steady state; 부하용량투여시 3일, 유지용량투여시 7일 11),12) ) 에도달한후측정된첫번째혈중농도값을 TDM1으로선택하고그다음측정된두번째혈중농도를 TDM2로선택하였다. 이때 TDM1과 TDM2때의투여용량은변경되었을수도있고같을수도있으며 TDM1만있는경우도있다. TDM1의분포에따라 TDM1 0.5 μg /ml인경우를그룹1(g1), 0.5 TDM1 1 μg /ml은 G2, 1 TDM1 5.5 μg /ml( 치료영역 ) 은 G3, 5.5 TDM1 10 μg /ml은 G4, TDM1 10 μg /ml은 G5으로분류해환자군을나누었다. 초기혈중농도 (TDM1) 가치료영역에도달하지못한 G1, G2, G4, G5에대해서각내원단위별로 2개의투여용량-TDM 쌍 (DOSE1-TDM1, DOSE2- TDM2) 을결정한후두쌍사이의투여용량변화량과혈중농도변화량을구했다 (ΔDOSE, ΔTDM)(Table 5A~8B). 그다음, 용량변화량 (ΔDOSE) 을분석하여각군별기준용량변화량 (x) 을설정한후, x이상 ( 또는초과 ) 과 x이하 ( 또는미만 ) 로증량 ( 또는감량 ) 한경우로소그룹으로나누었다. 각소그룹마다 TDM2값이치료영역내에들어온비율 (%, endpoint 1) 과증가 ( 또는감소 ) 된혈중농도변화량 (ΔTDM( μg /ml), endpoint 2) 을구했다. G1에서는 2 mg/kg/day, G2에서는 0.5 mg/kg/day, G4에서는 1 mg/kg/day, G5에서는 2 mg/kg/day을기준용량변화량으로설정했다. 보리코나졸은용량-혈중농도의상관관계가비선형적인특성을가지기때문에약동학적파라미터를구할수없어, 대신치료영역에도달한빈도가높은소그룹

4 이재은 : Voriconazole 의용량변경현황분석및제안 의평균증가량, 표준편차, 그리고다빈도의변경용량값을고려하여용량변경을제안했다. 본연구는보리코나졸의혈중농도가치료영역 (1 혈중농도 5.5 μg /ml) 내에도달하면약물의효과가있다는것을전제로하였기때문에약물의혈중농도에따른효과나이상반응여부는따로분석하지않았다. 3. 통계분석전체내원을대상으로범주형변수는빈도와분율, 연속형변수는평균과표준편차를제시하였다. TDM1을치료영역을기준으로분류한세군 (A: 치료영역미만 (G1, G2), B: 치료영역내 (G3), C: 치료영역초과 (G4, G5)) 간유의한차이가있는지범주형변수의경우카이제곱검정 (chi-square test), 연속형변수의경우분산분석 (one-way analysis of variance) 를이용하여확인하였다. 다음으로 G1, G2, G4, G5 내에서각각보리코나졸용량변경에따라구분한두소그룹간에 TDM 농도변화량에유의한차이가있는지 t-검정 (t-test) 또는윌콕슨부호순위검정 (Wilcoxon rank sum test) 을이용하였다. 그리고그소그룹간치료범위도달여부에유의한차이가있는지카이제곱검정또는피셔의정확검정 (Fisher s exact test) 을사용하여확인하였다. 통 계적유의수준은 0.05로하였으며, 모든통계분석은 SAS 프로그램 (version 9.4; SAS Institute, Cary, NC) 을이용하였다. 4. 연구대상자의보호본연구는연구대상자의안전및보호에관한사항등을포함한연구계획을본연구가실시된서울아산병원의기관생명위원회 (Institutional Review Board) 로부터승인 (IRB No.S ) 을받았으며, 의무기록지에기록된내용만을이용해분석하는후향적연구이기때문에연구대상자의동의는생략하였다. 연구결과 1. 연구대상자의특성 ABLE 프로그램으로추출한총내원은 779건이었다. 이중보리코나졸의혈중농도가항정상태에도달하지않을때측정된경우나, 병용주의, 병용금기약물을병용하거나간경화진단을받아제외된경우는 205건이며전체의 26.32% 를차지했다 (Table 1). 실질분석대상인 574건의특성은 Table 2에있다. 진료과는상위 8개, 동반질환은상위 12개를제시하였다. Table 1 Patient exclusion criteria Voriconazole TDM case (n) (%) Not in a steady-state 161 (20.67) Coadministered with Rifampicin 11 (1.41) Efavirenz 1 (0.13) Ritonavir 2 (0.26) Carbamazepine 1 (0.13) Rifabutin 11 (1.41) Phenytoin 4 (0.51) Diagnosed with liver cirrhosis 14 (1.80) Total 205 (26.32) (%)means a percent of total N which includes exclusion criteria

5 JKSHP, VOL.35, NO.3 (2018) Table 2 Main clinical characteristics of study patients Characteristics Total(N=574) Voriconazole TDM (%)*or± case (n) SD Gender Male 378 (65.85) Female 196 (34.15) Age (Mean±SD) ±14.16 Intensive Care Unit Yes 118 (20.56) Department Hematology 271 (47.21) Pulmonology 87 (15.16) Liver transplantation & hepatobiliary surgery 85 (14.81) Infectious disease 29 (5.05) Oncology 26 (4.53) Rehabilitation medicine 15 (2.61) General surgery 14 (2.44) Cardiology 10 (1.74) Concomitant Steroids 248 (43.21) medications Proton pump inhibitors(ppis) 300 (52.26) Comorbidities Aspergillosis (B44) 288 (50.17) Respiratory disorders in diseases classified eleswhere (J99) 209 (36.41) Personal history of allergy to drugs, medicaments and biological substances (Z88) 171 (29.79) Myeloid leukemia (C92) 169 (29.44) Essentialhypertension (I10) 157 (27.35) Transplanted organ and tissue status (Z94) 152 (26.48) Pneumonia, organism unspecified (J18) 126 (21.95) Non-insulin-dependent diabetes mellitus (E11) 130 (22.65) Other sepsis (A41) 105 (18.29) Agent resistant to vancomycin and related antibiotics (U81) 87 (15.16) Gastritis and duodenitis (K29) 79 (13.76) Acute renal failure (N17) 74 (12.89) * %: Percent of total study patients SD : Standard deviation Steroids: Deflazacort, Dexamethasone, Methylprednisolone, Prednisolone, Hydrocortisone, PPIs: Dexlansoprazole, Lansoprozole, Esomeprazole, Pantoprazole, Labeprazole Comorbidities: ICD-10 (International classification of diseases 10th version)

6 이재은 : Voriconazole 의용량변경현황분석및제안 2. 평균투여용량및평균초기혈중농도 (TDM1) 도가증가하는양상을보였다 (Fig. 1). 초기혈중농도값 (TDM1) 의분포에따라그룹 G1~G5 로나눈후그룹별보리코나졸투여용량의평균과표준편차를분석하였다 (Table 3). 각군의보리코나졸투여용량은다음과같았다. G1; 6.72±2.37 mg/kg/day, G2; 7.51±1.93 mg/kg/day, G3; 7.39±1.70 mg/kg/day, G4; 7.65±1.76 mg/kg/day, G5; 7.78±1.44 mg/kg/day 였다. G3을제외하고는 G1, G2, G4, G5 에서보리코나졸의투여용량이증가할수록초기혈중농 3. 초기혈중농도분포에따른여러요인들비교선행된연구문헌자료들을리뷰한결과보리코나졸의혈중농도분포에영향을줄수있다고판단한요인들은성별, 나이 (y), 체중 (kg), 키 (cm), 병동, 중환자실입원여부, 진료과, 진단명, 보리코나졸의투약목적, 병용금기또는병용주의약물, 신기능 (Scr, BUN, AST, ALT), 간기능 (T.BIL, Albumin), 이식, 투석여부, 염증 Table 3 Comparison of dose and initial serum concentration (TDM1) of voriconazole Group* Voriconazole TDM case (n) (%) Mean±SD Dose (mg/kg/day) Min Max μg Mean±SD Min Max TDM1 ( /ml) G ± ± G ± ± G ± ± G ± ± G ± ± Total ± ± * G1: TDM1 0.5 μg /ml, G2: 0.5 TMD1 1 μg /ml, G3: 1 TDM1 5.5 μg /ml, G4: 5.5 TDM1 10 μg /ml, G5: TDM1 10 μg /ml %: Percent of total study patients SD : Standard deviation TDM: Therapeutic drug monitoring Fig. 1 Distribution of serum voriconazole concentration (left) and TDM1 distribution of voriconazole dose by TDM1 (right)

7 JKSHP, VOL.35, NO.3 (2018) 수치 (CRP, WBC) 이다. 혈중농도가높거나낮게분포되는원인을파악하고자보리코나졸의초기혈중농도를크게치료영역미만, 이내, 이상의세개의군 ( 각각 A, B, C군 ) 으로다시나누었다 (Table 4). 이중 A, B, C군간에통계학적으로유의한차이가있던요소는나이, 중환자실입원여부, 스테로이드병용비율, 보리코나졸의투여용량, Scr, T.BIL, CRP수치였다. 세군을비교해보았을때나이가많을수록, 스테로이드병용을덜할수록, 보리코나졸의용량이클수록, CRP가높을수록보리코나졸의혈중농도가높게얻어지는것을확인했다. 참고적으로각군별보리코나졸의용량에따른혈중농도의선형적관련성을보기위해산점도로나타냈다 [ 부록 1]. 4. G1, G2, G4, G5의용량변경자료분석치료영역에도달하지못하거나초과한 G1, G2, G4, G5 에서용량을변경한적이있는내원은각각 39, 29, 59, 24건이었다. G1에서는 2 mg/kg/day 이하, G2에서는 0.5 mg/kg/day 이하, G4에서는 1 mg/kg/day 이상, G5 에서는 2 mg/kg/day 이상을기준으로소그룹을나누었고, 소그룹별건수는 25건 /14건, 18건 /11 건, 30건 /29건, 17건 /7건이었다. 각군의용량변화량에따른분포를보면, 정규분포곡선을이루지않고한쪽에치우쳐있다 [ 부록 2]. 따라서평균과표준편차가자료를대표한다고판단하기어려워다빈도의변경용량값도참고하여용량변경제안을하였다. 우선, 혈중농도가 0.5 μg /ml 미만인 G1에서투여용량을 2 mg/kg/day 증량한것을기준으로두소그룹으로나누었을때, 2 mg/kg/day 이하로증량한소그룹은증량후혈중농도가평균 1.12 μg /ml 만큼증가하였고 2 mg/kg/day 초과로증량한소그룹은평균 2.09 μg /ml 만큼증가하여두소그룹간혈중농도증가량이통계적으로유의한차이를보였다 (p=0.0236)(table 5A). 용량증량후치료영역내에포함되는비율을비교했을때 2 mg/kg/ day 이하증량과 2 mg/kg/day 초과증량했을때각각 56%, 93% 로 2 mg/kg/day 초과증량하였을때가치료영역내로많이도달했으며통계적으로유의한차이를보였다 (p=0.0283)(table 5B). 2 mg/kg/day 초과증량한그룹의평균증가량인 3.29 mg/kg/day와표준편차, 그리고대부분의자료가위치한변경용량값 (2-5 mg/kg/day) 을고려했을때 ( 부록 2A) 다음투여시 2-5 mg/kg/day 증량할것을권장한다 (Table 5B). 혈중농도가 0.5 μg /ml 이상 1 μg /ml 미만인 G2에서는 0.5 mg/kg/day 초과증량한군과이하증량한군의혈중농도증가량이통계적으로유의한차이를보였으며 (p=0.0061) 증량후혈중농도값이치료영역내에포함되는비율도각각 82%, 33% 로통계적으로유의한차이를보였다 (p=0.0112)(table 6A). 0.5 μg /ml 초과증량한소그룹의평균과표준편차, 그리고대부분의자료가위치한변경용량값을고려했을때 ( 부록 2B) 다음투여시 mg/kg/day 증량할것을권장한다 (Table 6B). 혈중농도가 5.5 μg /ml 이상 10 μg /ml 미만인 G4에서는 1 mg/kg/day 이상감량한소그룹 (ΔDOSE -1 mg/kg/day) 과미만감량한소그룹 (ΔDOSE -1 mg/kg/day) 의혈중농도감소량이통계적으로유의한차이를보였다 (p=0.0389)(table 7A). 감량후치료영역내에도달하는비율은 87% 와 72% 로유의한차이를보이지않았지만 (p=0.1959), 여전히 toxic level에남아있는비율이 7% 와 24% 로차이가있었다 (Table 7B). 1 mg/kg/day 이상감량한소그룹의혈중농도감소량과 toxic level에유지되는정도, 그리고대부분의자료가위치한변경용량값을고려했을때 ( 부록 2C), 이군은다음투약시 mg/kg/day 정도감량할것을권장한다. 혈중농도가 10 μg /ml 이상인 G5에서는 2 mg/kg/day 이상감량한소그룹 (ΔDOSE -2 mg/kg/day) 과미만감량한소그룹 (ΔDOSE -2 mg/kg/day) 의혈중농도감소량이통계적으로유의한차이를보였다 (p=0.0454)(table 8A). 감량후치료영역내에도달하는비율은 76% 와 43% 로통계적으로의미있는차이를보이지않았지만 (p=0.0819) 여전히 toxic level에남아있는비율이 12% 와 57% 이었다 (Table 8B). 2 mg/kg/day 이상감량한소그룹의평균과표준편차를반영하여 ( 부록 2D), 혈중농도가 10 μg /ml 이상일경우다음투약은생략하고그다음투약시 mg/kg/ day 정도감량할것을권장한다

8 이재은 : Voriconazole 의용량변경현황분석및제안 Table 4 Comparison of demographical, clinical, and biochemical characteristics according to initial serum concentration (TDM1) of voriconazole Characteristics G5 (0 TDM 1)(N=106) No. of visit (%) G6 (1 TDM 5.5)(N=332) No. of visit (%) G7(TDM 5.5)(N=136) No. of visit (%) Total (N=574) No. of visit (%) p- value* Gender Male 69 (65.09) 210 (63.25) 99 (72.79) 378 (65.85) Female 37 (34.91) 122 (36.75) 37 (27.21) 196 (34.15) Age ) Intensive Care Unit Yes 23 (21.70) 50 (15.06) 45 (33.09) 118 (20.56).0001 Department Hematology 47 (44.34) 156 (46.99) 68 (50.00) 271 (47.21) Pulmonology 16 (15.09) 51 (15.36) 20 (14.71) 87 (15.16) Liver transplantation & hepatobiliary surgery 19 (17.92) 40 (12.05) 26 (19.12) 85 (14.81) Infectious disease 5 (4.72) 22 (6.63) 2 (1.47) 29 (5.05) Oncology 3 (2.83) 17 (5.12) 6 (4.41) 26 (4.53) Rehabilitation medicine 5 (4.72) 8 (2.41) 2 (1.47) 15 (2.61) General surgery 6 (5.66) 6 (1.81) 2 (1.47) 14 (2.44) Cardiology 1 (0.94) 6 (1.81) 3 (2.21) 10 (1.74) Etc 4 (3.77) 26 (7.83) 7 (5.15) 37 (6.45) Concomitant medications Steroids 55 (51.89) 150 (45.18) 43 (31.62) 248 (43.21) Proton pump inhibitors 65 (61.32) 170 (51.20) 65 (47.79) 300 (52.26) Comorbidities Aspergillosis (B44) 51 (48.11) 173 (52.11) 64 (47.06) 288 (50.17) Respiratory disorders in diseases classified eleswhere (J99) Personal history of allergy to drugs, medicaments and biological substances (Z88) 40 (37.74) 131 (39.46) 38 (27.94) 209 (36.41) (32.08) 102 (30.72) 35 (25.74) 171 (29.79) Myeloid leukemia (C92) 25 (23.58) 99 (29.82) 45 (33.09) 169 (29.44) Essentialhypertension (I10) 23 (21.70) 94 (28.31) 40 (29.41) 157 (27.35) ransplanted organ and tissue status (Z94) 33 (31.13) 83 (25.00) 36 (26.47) 152 (26.48) Pneumonia, organism unspecified (J18) 20 (18.87) 75 (22.59) 31 (22.79) 126 (21.95) Non-insulin-dependent diabetes mellitus (E11) 24 (22.64) 78 (23.49) 28 (20.59) 130 (22.65) Other sepsis (A41) 21 (19.81) 51 (15.36) 33 (24.26) 105 (18.29)

9 JKSHP, VOL.35, NO.3 (2018) Characteristics G5 (0 TDM 1)(N=106) No. of visit (%) G6 (1 TDM 5.5)(N=332) No. of visit (%) G7(TDM 5.5)(N=136) No. of visit (%) Total (N=574) No. of visit (%) p- value* Comorbidities Agent resistant to vancomycin and related antibiotics (U81) 16 (15.09) 47 (14.16) 24 (17.65) 87 (15.16) Gastritis and duodenitis (K29) 20 (18.87) 45 (13.55) 14 (10.29) 79 (13.76) Acute renal failure (N17) 18 (16.98) 36 (10.84) 20 (14.71) 74 (12.89) Mean A SD Mean B SD Mean C SD Mean Total SD p- value* Voriconazole dose (mg/kg/day) ) Lab data Scr (Mean ± SD) ) BUN (Mean ± SD) AST (Mean ± SD) ALT (Mean ± SD) T.BIL (Mean ± SD) ) ALBUMIN (Mean ± SD) CRP (Mean ± SD) ) WBC (Mean ± SD) * p-value was estimated by chi-square test for caterogical variable, one-way analysis of variance for continuous variables. Etc : Thoracic & cardiovascular surgery, Otorhinolaryngology, Nephrology, Pediatric hematology & oncology, Rheumatology, Gastroenterology, Allergy, Chronic rhinosinusitis, Hepatobiliary pancreatic surgery, Gastric surgery and Endocrinology Comorbidities: ICD-10 (International classification of diseases 10th version) Missing data was excluded from the lab data analysis [Scr (N=67), BUN (N=68), AST (N=195), ALT (N=195), T.BIL(N=200), ALBUMIN (N=233), CRP(N=281), WBC(N=49)]. Extreme outlier was excluded from the analysis of AST and ALT (ast=7008.1, alt=2250.2). Table 5A Changes in the dose and serum concentration in G1 patients G1 ΔDOSE* N DOSE1 DOSE2 TDM1 TDM2 ΔTDM p- value 2 mg/kg/day ± ± ± ± ± (0.52±0.99) 2 mg/kg/day 2 (3.29±1.23) ± ± ± ± ±1.26 * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change ΔTDM = TDM2 - TDM1 = Voriconazole serum concentration change 2 mg/kg/day unless otherwise indicated p-value was estimated by t-test

10 이재은 : Voriconazole 의용량변경현황분석및제안 Table 5B Proportions of G1 patients who reached therapeutic range after dose change ΔDOSE* Within therapeutic range Not in therapeutic range Total p-value 2 mg/kg/day 14(56%) 11(44%) 25(100%) mg/kg/day (3.29±1.23) 13(93%) 1(7%) 14(100%) * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change 2 mg/kg/day unless otherwise indicated p-value was estimated by Fisher's exact test. Table 6A Changes in dose and serum concentration of voriconazole in G2 patients G2 ΔDOSE* N DOSE1 DOSE2 TDM1 TDM2 ΔTDM p- value 0.5 mg/kg/day ± ± ± ± ± (-0.06±0.23) 0.5 mg/kg/day ± ± ± ± ±1.75 (1.92±0.94) * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change ΔTDM = TDM2 - TDM1 = Voriconazole serum concentration change 0.5 mg/kg/day unless otherwise indicated p-value was estimated by Wilcoxon rank sum test. Table 6B Proportions of G2 patients who reached therapeutic range after dose change ΔDOSE* Within therapeutic range Not in therapeutic range Total p-value 0.5 mg/kg/day 6(33%) 12(6%) 18(100%) mg/kg/day (1.92±0.94) 9(82%) 2(18%) 11(100%) * 00%)day/dayeu - Dose1 = Voriconazole dose change 00%)day/daye unless otherwise indicated p-value was estimated by Chi-square test. 고찰보리코나졸은 1 혈중농도 5.5 μg /ml의좁은치료농도를갖는혈중농도모니터링대상약물이다. 보리코나졸의혈중농도가치료농도를넘을경우시력장애, 간독성, 심장독성같은부작용발생위험성이높고혈중농도가치료농도범위보다낮을경우치료효과가나타나지않아진균감염으로인해환자의상태가악화되므로혈중농도모니터링 (TDM) 활동이반드시필요하다는많은연구들이있었다. 13)-15) 약물의혈중농도 (trough concentration) 가 1 μg /ml 이하일경우 1 μg /ml 초과인경우보다치료효과가현저히떨어지며, 15) 한연구결과에의하면보리코나졸의혈중농도가 1.5 μg /ml 이상일경우 IFI (Invasive fungal infections) 가치료될확률이 85% 이며 4.5 μg /ml 이상일경우 15% 에서 NCI (National Cancer Institute) grade3 신경독성 ( 불안을동반한뇌병증, 불안, 정신착란, 환각, 근경련증 ) 이발생한다고보고된바있다. 16) 이러한이유로임상에서는보리코나졸투여시혈중농도를측정해용량을변경하고있지만지금까지많은

11 JKSHP, VOL.35, NO.3 (2018) Table 7A Changes in the dose and serum concentration of voriconazole in G4 patients G4 ΔDOSE* N DOSE1 DOSE2 TDM1 TDM2 ΔTDM p- value * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change ΔTDM = TDM2 - TDM1 = Voriconazole serum concentration change -1 mg/kg/day ± ± ± ± ± (-2.65±1.31) -1 mg/kg/day ± ± ± ± ±4.86 (-0.1±1.0) -1 mg/kg/day unless otherwise indicated p-value was estimated by t-test. Table 7B Proportions of G4 patients who reached therapeutic range after dose change ΔDOSE* Sub therapeutir range Within therapeutic range Supra therapeutic range Total p-value * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change -1 mg/kg/day 2(6%) 26(87%) 2(7%) 30(100%) mg/kg/day 1(3%) 21(72%) 7(24%) 29(100%) -1 mg/kg/day unless otherwise indicated p-value was estimated by Fisher's exact test. Table 8A Changes in the dose and serum concentration of voriconazole in G5 patients G5 ΔDOSE* N DOSE1 DOSE2 TDM1 TDM2 ΔTDM p- value * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change ΔTDM = TDM2 - TDM1 = Voriconazole serum concentration change -2 mg/kg/day ± ± ± ± ± (-3.39±0.79) -2 mg/kg/day ± ± ± ± ±5.34 (-0.3±1.9) -2 mg/kg/day unless otherwise indicated p-value was estimated by Wilcoxon rank sum test. Table 8B Proportions of G5 patients whose voriconazole level reached therapeutic range after dose change ΔDOSE* Sub therapeutir range Within therapeutic range Supra therapeutic range Total p-value * ΔDOSE: Dose2 - Dose1 = Voriconazole dose change -2 mg/kg/day 2(12%) 13(76%) 2(12%) 17(100%) mg/kg/day 0(0%) 3(43%) 4(57%) 7(100%) -2 mg/kg/day unless otherwise indicated p-value was estimated by Fisher's exact test

12 이재은 : Voriconazole 의용량변경현황분석및제안 연구들이특정질환, 병용약물등의영향요인유무에따른보리코나졸의초기투여용량을결정하고자했었다. 예를들면 2015년중국에서행해진성인중환자에서의보리코나졸의적절한투여용량을찾기위한연구에서는보리코나졸을 150 mg bid로투여했을때 79.54% 가 μg /ml 에도달하였고 200 mg bid로투여했을때 90.31% 가 μg /ml에도달해간독성위험이있음에도 200 mg bid 투여를권장했다. 경증, 중등도의감염의치료나예방요법을목적으로투여할경우간독성의위험이적고거의비슷한유효성을보이는 150 mg bid로투여할것을권장했다. 22) 그러나임상현장에서는보통식품의약품안전처 ( 식약처 ) 에서허가받은사용량 (200 mg bid) 으로투약을시작하고환자의상태와보리코나졸의혈중농도를모니터링하면서용량을변경하고있다. 치료영역에비해낮거나높은혈중농도가얻어졌을때용량변경에관한질문을약사에게하고있으나아직확실한가이드라인이없기에많은약사들이어려움을겪고있는것이사실이다. 그러나보리코나졸은환자의기저질환, CYP2C19의유전자형, 병용약물등의영향을받아약물의혈중농도가변한다고알려져있어 TDM이필요한약물임에도가이드라인을정하기가쉽지않았다. 본연구에서보리코나졸의용량변경현황분석대상자를선정하고용량변경제안을하는데있어실제로보리코나졸의혈중농도에큰영향을주는요인들을가려내는과정이중요했다. 알려진여러요인들에관한문헌조사를통해보리코나졸의혈중농도에영향을미친다고보는요소를선정했다. 보리코나졸은 CYP2C19에의해대사되는약물이기때문에리팜피신, 리파부틴같은 CYP 유도제를병용할때보리코나졸의혈중농도는감소하고수소펌프차단제 (PPI; Proton Pump Inhibior) 를병용할경우보리코나졸의혈중농도는증가한다. 4),17) 실제로한연구결과리팜피신은 CYP2C9의유전자형에상관없이 CYP2C9의양을약두배증가시켜 18) 보리코나졸의최고혈중농도 (Cmax; the maximum concentration) 와누적농도 (AUC; area under the curve, 곡선하면적 ) 를 99% 정도감소시키기때문에보리코나졸의약물효과는거의나타나지않았다. 19) IFI 위험이높은혈액학적장애를가진환자들을대상으로 CYP유도제병용 과 CYP억제제인 PPI 병용시혈중농도를모니터링한연구결과 PPI를병용할경우 25% 가보리코나졸의독성을경험한반면, 병용하지않을경우소수만이보리코나졸의독성을보였다. 프레드니솔론, 덱사메타손등의스테로이드를병용할경우보리코나졸의혈중농도는병용하지않을때보다낮아지며리토나비어병용시보리코나졸의혈중농도는증가했다. 4),11) CYP유도제와 CYP억제제를모두병용할경우보리코나졸의혈중농도는감소하는결과를보였다. 17) 보리코나졸의대사효소인 CYP2C19의유전자형은많은연구에서개인별보리코나졸의혈중농도가다르다는것을설명하는주요영향요인으로연구되고있다. 1,000명의보리코나졸투여환자의처음 7일간의혈중농도를분석한한연구결과 CYP2C19의유전자형이 PM (Poor metabolizer)/hem (Heterozygous extensive metabolizer) 인경우보다 EM (Extensive metabolizer)/hum (Homozygous extensive metabolizer) 유전자형일경우보리코나졸의평균혈중농도가낮게유지되었다. 20),21) 그러나 2014년 CYP2C19 유전자형에따른보리코나졸의적정용량을찾고자하는연구에서 CYP2C19 유전자형에따른혈중농도의차이는정상인에서만뚜렷하게보인다는결과가있었고 13) 서울아산병원에서는아직까지 CYP2C19의분석이이루어진 N수가충분하지않아이번연구에서는 CYP2C19에따른보리코나졸의혈중농도분석은하지않았다. 신기능에따른보리코나졸의용량을고려해보면, Serum Creatinine이 2.5 ml/dl을초과할정도로신기능이떨어질경우주사제에포함되어있는용해제인 SBECD (Sulphobutyleter-beta-cyclodextrin) 가축적되어신기능을악화시킬수있어경구제를사용하는것이추천되나, 23) 신기능에따라보리코나졸의약동학적성질 (pharmacokinetic) 이달라지지않기때문에용량조절이필요하지않다. 9),24) 간기능저하정도에따라보리코나졸의용량을조절하도록권고하는연구들이있는데, 한연구결과 Child- Pugh Class A, B인간기능저하환자에서는유지용량을 50% 감량해간기능손상을줄이도록권고하고있다. 25) Child-Pugh Class C 환자군을대상으로한연구에서는심각한간손상이있는환자들을위한용량조절이필요하지만확실히증명할수있는방법이없어

13 JKSHP, VOL.35, NO.3 (2018) 여러번의 TDM을통해서용량을정해야한다고한다. 5) 간기능저하시보리코나졸의혈중농도가크게영향을받는것이확실하기때문에간기능저하환자들은별도로분석해야할필요가있다고생각되어본연구에서는포함하지않았다. 이러한과거문헌조사를통해보리코나졸의혈중농도에영향을줄수있다고판단한요인들 ( 성별, 나이, 체중, 키, 병동, 중환자실입원여부, 진료과, 진단명, 보리코나졸의투약목적, 병용금기또는주의약물, 신기능 (Scr, BUN), 간기능 (AST, ALT, T.BIL, Albumin), 이식, 투석여부, 염증수치 (CRP, WBC) 중, 연구결과 A 군 ( 치료영역미만 ), B군 ( 치료영역내 ), C군 ( 치료영역초과 ) 간통계적으로유의한차이를보이고경향성을나타내는요소는나이, 스테로이드병용비율, 보리코나졸의투여용량, CRP 수치였고이러한결과는선행연구들과같은결과를보였다. 초기혈중농도가치료영역미만을나타낸 A군과치료영역초과의혈중농도를갖는 C군만을비교했을때, C 군이 A군보다 Scr 수치가낮고 (A:1.16±1.19, C: 1.10 ±0.57 mg/dl), T.Bil이높았으며 (A:3.15±6.31, C:4.72±7.27 mg/dl) 이는 A, B, C군에서통계적으로유의한차이를보였지만 (p-value; Scr: 0.030, T.Bil: 0.016), A, B, C군전체의경향성을봤을때보리코나졸의혈중농도와 Scr( 또는 T.Bil) 사이에경향성을보이지않았고, Scr이측정되지않은경우가 67건, T.Bil의결측건수는 200건으로많아각군간에통계적으로유의한차이를보인다는결과는신뢰할수없다고판단했다. 참고적으로 Lab수치들의결측값은총 574 건중 Scr이 67 건, BUN이 68 건, AST 195건, ALT 195건, T.BIL 200건, Albumin 233건, CRP 281건, WBC 49건이었다. A, B, C군에서경향성을보였던 CRP도유의한차이가있는결과를얻었지만반정도가결측이어서신뢰성이떨어질것으로생각된다. 중환자여부도 A, B, C군에서통계적으로유의한차이가있었지만경향성이설명되지않아약물의혈중농도의영향요인에서배제되었다. 본연구에서수집된임상자료들에는약물의혈중농도가치료영역보다낮음에도오히려감량한경우또는혈중농도가높음에도더증량한경우를포함했기때문에용량변경의평균값및표준편차에도영향을미쳤을 것이다. 또한실제로다양한변수들을조사하였지만많은검사수치들에결측치가많고경향성이설명되지않아용량조절의기준을제시할때고려대상요인이되지못한점이아쉬운점으로남는다. 뿐만아니라최종적으로제안한가이드대로변경하지않았음에도치료역에도달한경우가상당히있었고, 용량-혈중농도간비선형적인특성을갖는약물의약동학적파라미터인최대대사속도 (Vmax), Km을산출하여청소율을구하는등공인된방법으로진행한연구가아니기때문에본연구에서도출된결론이공식적인가이드가되기에는다소위험할수있다. 그럼에도불구하고본연구는장기간의다양한임상데이터를이용하여평균용량및혈중농도를제시했고통계적으로유의한차이를보이는결과값을얻어임상약사들이참고할만한자료를얻었으며, 이를바탕으로용량변경제안을했다는점에서큰의의가있다고본다. 본연구에서는간경화진단환자, 병용금기, 병용주의약물을병용한환자군을제외하여분석했는데, 향후이번에제외된대상군들에대해서임상자료를충분히수집하여분석한다면좀더다양한환자들을위한가이드를제시할수있을것으로생각된다. 본연구는약물의혈중농도가치료영역에도달하면치료효과가충분히있을것이라는전제하에진행되었기때문에본연구에서제시한용량대로변경했을때약물의효과와부작용을모니터링하는전향적연구가진행된다면의미있을것이라생각한다. 결론보리코나졸의초기혈중농도분포별용량변경후치료영역내에들어온비율및혈중농도변화량, 그리고용량변경제안은다음과같다. 1. 혈중농도가 0.5 μg /ml 미만일경우, 2 mg/kg/day 이하증량시평균 1.12 μg /ml 증가, 치료영역에 56% 도달, 2 mg/kg/day 초과증량시평균 2.09 μg /ml 증가 (p=0.0236), 치료영역에 93% 도달한다 (p=0.0283). 다음투여시 2-5 mg/kg/day 증량이추천된다. 2. 혈중농도가 0.5 μg /ml 이상 1 μg /ml 미만일경우,

14 이재은 : Voriconazole 의용량변경현황분석및제안 0.5 mg/kg/day 이하증량시평균 0.58 μg /ml 증가, 치료영역에 33% 도달, 0.5 mg/kg/day 초과증량시평균 1.94 μg /ml 증가 (p=0.0061), 치료영역에 82% 도달한다 (p=0.0112). 다음투여시 mg/kg/day 증량이추천된다. 3. 혈중농도가 5.5 μg /ml 이상 10 μg /ml 미만일경우, 1 mg/kg/day 이상감량시평균 4.21 μg /ml 감소, 치료영역에 87% 도달, 1 mg/kg/day 미만감량시평균 2.05 μg /ml 감소 (p=0.0389), 치료영역에 72% 도달한다 (p=0.1959). 다음투여시 mg/kg/day 감량이추천된다. 4. 혈중농도가 10 μg /ml 이상일경우 2 mg/kg/day 이상감량시평균 8.41 μg /ml 감소, 치료영역에 76% 도달, 2 mg/kg/day 미만감량시 3.66 μg /ml 감소 (p=0.0454), 치료영역에 43% 도달한다 (p= ). 다음투약은생략하고그다음투약시 mg/kg/day 감량이추천된다. 단, 용량변경시고령일수록, CRP가증가할수록보리코나졸의혈중농도가증가하고스테로이드를병용할수록보리코나졸의혈중농도가감소한다는점을고려해용량을변경한다. 참고문헌 1) Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3): ) Korea pharmaceutical information center. KPIC Drug Information. [updated 2014 June; cited 2017 July 1]. Available from: ail.asp?idx= ) Yamada T, Mino Y, Yagi T et al. Saturated metabolism of voriconazole N-Oxidation resulting in nonlinearity of pharmacokinetics of voriconazole at clinical doses. Biol Pharm Bull. 2015;38(10): ) Dolton MJ, Ray JE, Chen SC et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56(1`1): ) Weiler S, Zoller H, Graziadei I et al. Altered pharmacokinetics of voriconazole in a patient with liver cirrhosis. Antimicrob Agents Chemother. 2007;51(9): ) Van Wanrooy MJ, Span LF, Rodgers MG et al. Inflammation is associated with voriconazole trough concentrations. Antimicrob Agents Chemother. 2014;58(12): ) Han K, Bies R, Johnson H et al. Population pharmacokinetic evaluation with external validation and Bayesian estimator of voriconazole in liver transplant recipients. Clin Pharmacokinet. 2011;50(3): ) Han K, Capitano B, Bies R et al. Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients. Antimicrob Agents Chemother. 2010;54(10): ) Abel S, Allan R, Gandelman K et al. Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies. Clin Drug Investig. 2008;28(7): ) Radej J, Krouzecky A, Stehlik P et al. Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration. Ther Drug Monit. 2011;33(4): ) Lazarus HM, Blumer JL, Yanovich S et al. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol. 2002;42(4): ) Denning DW, Ribaud P, Milpied N et al

15 JKSHP, VOL.35, NO.3 (2018) Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. 2002;34(5): ) Moriyama B, Kadri S, Henning SA et al. Therapeutic drug monitoring and genotypic screening in the clinical use of voriconazole. Curr Fungal Infect Rep. 2015;9(2): ) Park WB, Kim NH, Kim KH et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012;55(8): ) Elewa H, El-Mekaty E, El-Bardissy A et al. Therapeutic drug monitoring of voriconazole in the management of invasive fungal infections: A critical review. Clin Pharmacokinet. 2015;54(12): ) Pascual A, Csajka C, Buclin T et al. Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis. 2012;55(3): ) Cojutti P, Candoni A, Forghieri F et al. Variability of voriconazole trough levels in haematological patients: Influence of comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers. Basic Clin Pharmacol Toxicol. 2016;118(6): ) Vormfelde SV, Brockmoller J, Bauer S et al. Relative impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy volunteers. Clin Pharmacol Ther. 2009;86(1): ) Baciewicz AM, Chrisman CR, Finch CK et al. Update on rifampin, rifabutin, and rifapentine drug interactions. Curr Med Res Opin. 2013;29(1): ) Dolton MJ, Mikus G, Weiss J et al. Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing. J Antimicrob Chemother. 2014;69(9): ) Lee S, Kim BH, Nam WS et al. Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. J Clin Pharmacol. 2012;52(2): ) Chen W, Xie H, Liang F et al. Population pharmacokinetics in China: The dynamics of intravenous voriconazole in critically ill patients with pulmonary disease. Biol Pharm Bull. 2015;38(7): ) Hamada Y, Tokimatsu I, Mikamo H et al. Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. J Infect Chemother. 2013;19(3): ) FDA Antiviral Drugs Advisory Committee- Briefing document for voriconazole (oral and intravenous formulations) [updated 2001 October 4; cited 2017 June 1]. Available from: dockets/ac/01/briefing/3792b2_01_pfizer.pdf. 25) Cota JM, Burgess DS. Antifungal dose adjustment in renal and hepatic dysfunction: Pharmacokinetic and pharmacodynamic considerations. Curr Fungal Infect Rep. 2010;4(2):

16 이재은 : Voriconazole 의용량변경현황분석및제안 [ 부록1] Scatter plot revealing relationship between dose and serum concentration of voriconazole by initial serum concentration DOSE2*TDM1 DOSE2*TDM2 DOSE(2-1)*TDM(2-1) G1 G2 G4 G5 DOSE(2-1): Dose2 - Dose1 = Voriconazole dose change TDM(2-1): TDM2 - TDM1 = Voriconale serum concentration change

17 JKSHP, VOL.35, NO.3 (2018) [ 부록 2] Frequency distribution of TDM2 within therapeutic range by dose change of voriconazole. 2A. G1 2B. G

18 이재은 : Voriconazole 의용량변경현황분석및제안 2C. G4 2D. G