臨床藥理學會誌第 15 卷第 1 號 2007 Kor J Clin Pharmacol Ther 2007;15(1):37-45 건강한한국인피험자에서베실산베포타스틴의약동학특성에대한연구 1 서울대학교의과대학약리학교실및서울대학교병원임상약리실, 2 공군항공우주의료원연구부 3 울산대학교의과대학임상약리학교실및서울아산병원임상약리학과 김보형 1, 정재용 2, 김정렬 1, 임경수 1, 임형석 3, 유경상 1, 장인진 1, 신상구 1 =Abstract= Pharmacokinetic Characteristics of Bepotastine Besilate in Healthy Subjects Bo-Hyung Kim 1, Jae-Yong Chung 2, Jung-Ryul Kim 1, Kyoung Soo Lim 1 Hyeong-Seok Lim 3, Kyung-Sang Yu 1, In-Jin Jang 1, Sang-Goo Shin 1 1 Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine and Hospital 2 Department of Research, Aerospace Medical Center, Republic of Korea Air Force 3 Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine and Asan Medical Center Background: Bepotastine besilate is a non-sedating, second-generation H 1-antagonist. It is known to be rapidly absorbed after oral administration and negligibly distributed to the brain. This study aimed to assess pharmacokinetic (PK) characteristics and safety of bepotastine besilate after oral administration in Korean healthy subjects. Methods: An open, single dose, parallel group, dose-escalation study was performed in sixteen healthy subjects. Two groups of eight subjects received either 10 or 20 mg dosage, respectively. Blood samples for PK assessments were collected till 24 hours after oral administration of bepotastine besilate. For safety assessments, clinical laboratory tests, vital signs, physical examinations, and 12-lead ECGs (electrocardiographies) were measured. Results: The average area under the concentration-time curves from time zero to infinity (AUC) were 397.12 ± 28.56 (Mean ± SD) μg h/l for the 10 mg group, and 776.80 ± 88.48 μg h/l for the 20 mg group. The values of average C max were 97.19 ± 22.72 μg/l and 188.79 ± 30.39 μg/l in the 10 mg and 20 mg group, respectively. AUC and C max appeared to increase proportionally with the dose, and dose-normalized AUC and C max were similar between 10 mg and 20 mg dosing groups (t-test, P=0.647 647 and 0.777, respectively). Only one adverse event (hordeolum) was reported during this trial. No clinically significant abnormalities were observed in laboratory tests, vital signs or ECG measurements. Conclusions: Bepotastine besilate C max and AUC values proportionally increased with increasing dose. Bepotastine besilate was generally safe and well tolerated with only a mild adverse event. Key words: Bepotastine besilate, Pharmacokinetics, Linearity. 서론 알레르기성비염은 immunoglobulin E (IgE) 매 개염증반응으로생기는재채기, 콧물, 코막힘, 코가려움등의증상을보이는코점막질환이다. 전세계적으로인구의 20~30% 가앓고있는이질환의 * 본연구는서울대학교병원위탁연구비 (06-2003-007-0) 지원에의하여이루어졌음. 교신저자 : 장인진서울시종로구연건동 28 (110-744) 서울대학교의과대학약리학교실및서울대학교병원임상약리실전화번호 : 02-740-8290, 팩스 : 02-745-7996, E-mail: ijjang@snu.ac.kr 37
김보형외 : 건강한한국인피험자에서베실산베포타스틴의약동학특성에대한연구 국내유병률은약 20% 정도로알려져있다 1). 알레르기성비염의반응은조기반응과후기반응으로나눌수있으며, 조기반응은항원에노출되고 1시간이내에나타나는것으로비만세포 (mast cell) 와호염기구가 IgE-매개항원반응에의해서화학매개체들을분비하여나타난다 2). 조기반응을보인환자중약 50% 는 4~8시간에후기반응을나타낸다. 후기반응에서는 T 세포, 호산구등백혈구의침윤과활성화를볼수있으며 3), Th 2 세포에서분비되는사이토카인들은후기반응을포함한만성염증반응의중요한매개체로작용한다 4). 이중비만세포나호염기구에서분비되는히스타민은비염증상의가장중요한매개체로알려져있으며히스타민수용체와결합하여혈관을확장시키고혈관투과성을증가시킨다 5). 또한부교감신경을자극하여분비선의분비를증가시키고감각신경의말단을자극하여가려움증, 재채기, 분비물증가를일으킨다. 그러므로알레르기성비염치료시, 중증도에관계없이 H 1 히스타민수용체길항작용이있는항히스타민제가널리사용되고있으며, 가려움증, 재채기, 분비물증가를효과적으로감소시켜높은임상효과를나타내고있다 6). 베실산베포타스틴 (bepotastine besilate, (+)-(S)- 4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy] piperidino}butyric acid monobenzenesulfonate, 타리온정, 동아제약 ) 은 H 1 히스타민수용체길항제로서, 알레르기성비염의주요한알레르기반응으로여겨지고있는 I형알레르기반응과알레르기성염증에있어서특유하게관찰되는염증부위에의호산구침윤을억제한다. I형알레르기반응은특정항원에감작된이후생성된특이항체가비만세포에결합되어이후체내에들어오는같은항원에대하여수분내로일어나는면역반응을의미하며 5), 베포타스틴은혈관투과성항진및평활근수축에관여하는히스타민에대하여길항작용을하여효과를나타낸다. 한편, 알레르기성비염에서 특이적으로관찰되는호산구의기능은각종 cytokine 에의해조절되는데, 특히 IL-5는호산구의수명연장, 염증부위에의유주활성 (migratory activity) 의증강등에관여하는것으로보고되어있다 5). 베포타스틴은또한이 IL-5의생성을억제하여호산구의활성화를억제하는것으로생각된다. 본약물은일본내제약회사에서합성되어일본내에서사용을허가받은약물로서, 알레르기성비염이외에도만성두드러기, 피부질환에수반된소양증 ( 습진 피부염, 피부소양증, 양진 ) 에대한치료제로사용되고있다. 한국인환자에게베실산베포타스틴을적절하게투여하기위해서는한국인에서의임상시험결과, 즉 가교자료 (bridging data) 를이용하여외국의임상시험자료집을한국인에외삽 (extrapolation) 하는방법을고려할수있다. 본연구는한국인에서의가교자료생성목적으로, 건강한한국인남성피험자에게베실산베포타스틴 10 mg, 20 mg을단회투여후용량에따른약동학적특성및안전성을평가하고자하였다. 연구대상및방법 1. 연구대상본연구에자의로참여를결정하고서면동의한총 16명의건강한성인남성을대상으로하였다. 본연구는서울대학교병원의학연구윤리심의위원회 (institutional review board, IRB) 의승인을받은후시행되었다. 2. 연구설계본연구는공개 (open), 단회투약 (single), 단계적증량형태 (dose-escalation) 의임상시험으로설계되 38
B. H. Kim et al.: Pharmacokinetic characteristics of bepotastine besilate in healthy subjects 었으며각용량군 ( 베실산베포타스틴 10, 20 mg) 에각각 8명을배정하여임상연구를실시하였다. 병력조사, 활력징후, 신체검진, 임상실험실검사 ( 혈액학검사, 혈액화학검사, 소변검사 ), 면역학적검사 (IgE), 약물스크리닝검사, 혈청검사, 심전도등을통하여건강하며체중이표준체중의 ± 20% 이내인피험자를선정하였다. 모든피험자는투약하루전저녁에서울대학교병원임상시험센터에입원한후익일투약직전에활력징후, 심전도검사, 신체검진, 임상실험실검사를받았다. 투약당일아침, 베실산베포타스틴 ( 타리온정 10mg, 동아제약 ) 을물 100 ml와함께경구로투약후 4시간이상공복상태를유지하였으며, 24시간이경과한후활력징후, 심전도검사, 신체검진, 임상실험실검사를실시하여안전성을확인한후퇴원하였다. 이후투약후 8-9일째임상시험센터외래에내원하여활력징후, 심전도검사, 신체검진, 임상실험실검사를실시하여임상연구종료전안전성을추가로평가하였다. 투약전약동학채혈을위해좌측상완정맥에정맥카데터 (venous catheter) 를거치시켰다. 또한, 베실산베포타스틴이경구로투약된시점을 0시간으로정의하였으며, 투약직전및투약후 0.5, 1, 2, 3, 4, 6, 10 그리고 24시간에각각약 8 ml씩혈액을채취하였다. 채취된혈액은 heparinized tube에취하여잘섞은후, 1시간내에 4 냉장상태에서 3000 rpm(1500g) 으로 10분간원심분리하였다. 원심분리후 20분이내에혈장을 polypropylene tube 에취하였고분석시까지 -20 에냉동보관하였다. 3. 농도측정방법혈장시료로부터베실산베포타스틴의농도는액체크로마토그래피 (liquid chromatography, LC) 에질량분석기 (tandem mass spectrometry, MS/MS) 가연결된 LC/MS/MS를이용하여분석하였다. 내부표준물질 (internal standard, IS) 로염산세티리딘 (chloride cetridine) 을사용하였다. 혈장 0.1 ml에내부표준물질을넣고 OASIS HLB를이용하여용출시킨후, 질소기류하,50 에서증발건조하였다. 잔류물에이동상 0.3 ml를가해교반하여용해하고이것을시료용액으로하였으며, 시료용액 15 μl를 LC/MS/MS에주입하여분석하였다. 컬럼은 Symmetry C18( 입자크기 5 μm, 내부지름 길이 : 2.1 150 mm, Waters Corporation, MA, USA) 을사용하였다. 40 의컬럼온도에서이동상으로 10 mm ammonium acetate : acetonitrile 를 67:33 (volume/ volume) 으로섞어사용하였다. 질량분석기 (mass spectrometer) 는 API3000 (Applied Biosystems, UK) 를이온화법 (positive ion electrospray ionization (ESI) using multiple reaction monitoring (MRM)) 으로이용하였다. 혈장베실산베포타스틴측정을위한표준검량선은 0.2~200 ng/ml의농도범위로작성하였으며얻어진크로마토그램에서내부표준물질의피이크면적에대한베실산베포타스틴의피이크면적비를구하여미리작성한검량선으로부터혈장중베실산베포타스틴의농도를구하였다. 상기와같은방법으로 validation 을시행한후시료를분석하였다. 4. 약동학적분석 WinNonlin 5.0.1 (Pharsight Co, CA, USA) 프로그램을이용하여비구획약동학분석 (non-compartmental pharmacokinetic analysis) 으로약동학파라미터를산출하였다. 구체적으로시간경과에따른혈중약물농도의변화양상을 linear 혹은 log-linear 형태로표현하였고 log-linear 혈중농도-시간곡선의말단소실부선형회귀직선의기울기로부터소실속도상수 (k el) 을구하였다. 투약후 24시간까지베실산베포타스틴의혈중농도-시간곡선하면적 (area under 39
김보형외 : 건강한한국인피험자에서베실산베포타스틴의약동학특성에대한연구 Table 1. Demographic characteristics of the 16 healthy male subjects Characteristics Group Total 10mg Group 20mg Group (n=16) (n=8) (n=8) p-value Age (yr) 24.3 ± 1.8 24.1 ± 2.4 24.2 ± 2.1 * 0.778 Height (cm) 177.0 ± 4.8 173.6 ± 3.8 175.3 ± 4.5 * 0.153 Weight (kg) 72.7 ± 4.5 65.8 ± 7.6 69.2 ± 7.0 * 0.016 Smoking No 3 6 Yes 5 2 0.315 Drinking No 2 1 Yes 6 7 1.0 Caffeine No 2 2 Yes 6 6 1.0 All Values(Age, Height, Weight) are presented as mean ± standard deviation (SD) * Wilcoxon rank sum test Fisher s exact test the concentration-time curve, AUC 0-24) 은사다리꼴방식으로산출하였으며다음식을사용하여 AUC, 겉보기청소율 (CL/F) 및겉보기분포용적 (Vd/F) 등의약동학결과를산출하였다. 또한, 약동학결과산출에필요한채혈시간의적절성을고찰하기위해각피험자의 AUC extra(%) 를산출하였다. AUC = AUC 0-24 + C24/k el (C24: observed concentration at 24h after drug administration) CL/F = Dose administered orally (10 mg or 20 mg) / AUC Vd/F = (CL/F) (1/k el) AUC extra={(auc-auc 0-24)/AUC)} 100, % 최고혈중농도 (maximum observed concentration, C max) 및최고혈중농도도달시각 (time to maximum observed concentration, T max) 은실측값을활용하였고 C max 와 AUC의경우아래와같이베실산베포타스틴투여량으로표준화하여용량군간약동학결과비교에이용하였으며, 소실반감기 (t 1/2) 는다음의식을이용하여산출하였다. AUC/D = AUC / Dose C max/d = C max / Dose t 1/2 = ln(2) / k el 5. 통계분석 통계분석은 SPSS 12.0 (SPSS Korea, Seoul, Korea) 소프트웨어를사용하여모든피험자에대한결과및각용량군별로요약통계치를산출하였다. Plasma Concentration (μg/l) 200 150 100 50 0 0 5 10 15 20 25 Time (h) 10mg (n=8) 20mg (n=8) Figure 1. Mean (± standard deviation) plasma bepotastine besilate concentration-time profiles after single oral administration of 10 mg or 20 mg bepotastine besilate in 16 healthy male subjects (Bars, standard deviations) 40
B. H. Kim et al.: Pharmacokinetic characteristics of bepotastine besilate in healthy subjects Table 2. Pharmacokinetic results of bepotastine besilate after a single oral administration of 10 mg or 20 mg dose in 16 healthy male subjects ID T max C max AUC 0-24 AUC t 1/2 Vd/F CL/F MRT inf (h) (μg/l) (μg h/l) (μg h/l) (h) (L) (L/h) (h) DT101 1.00 120.90 434.79 438.63 3.80 125.00 22.80 4.70 DT102 1.00 85.10 396.76 399.27 3.48 125.75 25.05 4.57 DT103 1.00 81.20 407.64 413.92 4.35 151.69 24.16 5.28 DT104 1.00 84.60 352.28 357.61 4.62 186.30 27.96 4.77 DT105 1.00 93.00 388.05 391.75 3.66 134.62 25.53 5.25 DT106 1.00 103.70 414.81 420.27 4.21 144.52 23.79 4.95 DT107 1.03 70.40 353.51 357.46 3.92 158.13 27.97 5.08 DT108 1.00 138.60 395.47 398.03 3.55 128.62 25.12 4.33 Mean 97.19 392.91 397.12 3.95 144.33 25.30 4.87 SD 22.72 28.53 28.56 0.41 20.93 1.86 0.33 Median 1.00 89.05 396.12 398.65 3.86 139.57 25.09 4.86 Range 1.00~ 70.40~ 352.28~ 357.46~ 3.48~ 125.00~ 22.80~ 4.33~ 1.03 138.60 434.79 438.63 4.62 186.30 27.97 5.28 DT201 1.00 179.00 767.39 773.78 3.69 137.73 25.85 4.61 DT202 2.02 202.00 910.95 914.06 3.08 97.33 21.88 4.27 DT203 1.00 163.60 740.07 748.53 3.91 150.63 26.72 5.20 DT204 1.00 207.80 892.01 897.95 3.43 110.30 22.27 4.69 DT205 2.00 218.60 772.58 777.36 3.68 136.56 25.73 4.46 DT206 1.00 185.70 662.37 670.45 4.31 185.45 29.83 4.49 DT207 1.00 221.60 743.96 746.14 3.03 117.06 26.80 3.91 DT208 2.00 132.00 682.82 686.12 2.86 120.21 29.15 5.34 Mean 188.79 771.52 776.80 3.50 131.91 26.03 4.62 SD 30.39 89.05 88.48 0.49 27.50 2.85 0.47 Median 1.00 193.85 755.68 761.16 3.56 128.39 26.29 4.55 Range 1.00~ 132.00~ 662.37~ 670.45~ 2.86~ 97.33~ 21.88~ 3.91~ 2.02 221.60 910.95 914.06 4.31 185.45 29.83 5.34 T max: Time to maximum observed concentration C max: Maximum observed concentration AUC 0-24: Area under the concentration-time curve, 0-24h AUC: AUC 0-24 + C24/k el (C24: observed concentration at 24h after drug administration, kel: elimination rate constant), area under the time-concentration curve extrapolated to infinity t 1/2: Terminal elimination half-life Vd/F: Apparent volume of distribution CL/F: Apparent clearance MRT inf: Mean residence time of drug in the body, extrapolated to infinity 인구학적특성의경우, 임상시험에참여한피험자의연령, 신장, 체중, 흡연, 음주및카페인함유음료의섭취여부등에대해서각용량군간기술통계학적으로제시한후, 용량군간차이를비교하였다. 개별피험자의약동학결과는기술통계학적으 로제시하였고, 약동학적선형성을평가하기위해 AUC/D, C max/d, Vd/F, CL/F 그리고 t 1/2 에대하여정규성검정 (normality test) 을실시한후, 정규분포여부에따라용량군간 t-검정혹은, 윌콕슨순위합검정 (Wilcoxon rank sum test) 을실시하였 41
김보형외 : 건강한한국인피험자에서베실산베포타스틴의약동학특성에대한연구 Table 3. Statistical comparisons of pharmacokinetic results for evaluation of bepotastine besilate pharmacokinetic linearity between 10 mg and 20 mg dosing group 10 mg Group 20 mg Group P-value * AUC (μg h/l) 397.12 ± 28.56 776.80 ± 88.48 - Cmax (μg/l) 97.19 ± 22.72 188.79 ± 30.39 - AUC/dose (μg h/l/mg) 39.71 ± 2.86 38.84 ± 4.42 0.647 * Cmax/dose (μg/l/mg) 9.72 ± 2.27 9.44 ± 1.52 0.777 * t1/2 (h) 3.95 ± 0.41 3.50 ± 0.49 0.067 CL/F (L/h) 25.3 ± 1.9 26.0 ± 2.8 0.553 Vd/F (L) 144.33 ± 20.93 131.91 ± 27.50 0.327 * Comparison of values using independent sample t test between 10 mg and 20 mg dosing group 1000 800 regression line 95% confidence interval 250 200 regression line 95% confidence interval AUC (μg*h/l) 600 400 C max (μg/l) 150 100 200 50 0 0 0 10 20 30 Dose (mg) 0 10 20 30 Dose (mg) Figure 2. Assessment of dose proportionality for AUC and Cmax after single oral administration of 10 mg or 20 mg bepotastine besilate respectively. Left: AUC versus Dose (adjusted R-square: 0.90, P-value: <0.0001), Right: Cmax versus Dose (adjusted R-square: 0.75, P-value: <0.0001) 다. 또한, 베실산베포타스틴증량에따른 AUC, C max 의변화양상에대해선형회귀분석을실시하였다. 결과베실산베포타스틴 10 mg, 20 mg 투여군각 8명의인구학적정보에대하여기술통계학적으로분석한결과, 체중을제외한연령, 신장등의용량군간통계적으로유의한차이는없었다 (Table 1). 베실산베포타스틴평균혈중농도는약물투여 1 시간후최고농도에이른후빠른소실경향을보였으며투여량이증가함에따라혈중농도도비례적으로증가하는양상을보였다 (Figure 1). 10mg 용량군과 20mg 용량군의약동학적특성을요약하면 AUC( 평균 ± 표준편차 ) 는각각 397.12 ± 28.56 μg h/l, 776.80 ± 88.48 μg h/l 이었으며, C max( 평균 ± 표준편차 ) 는각각 97.19 ± 22.72 μg/l, 188.79 ± 30.39 μg/l이었다 (Table 2). 또한 AUC extra 의 10mg 용량군및 20mg 용량군의중앙값 ( 범위 ) 은각각 1.03% (0.63~1.52%), 0.64% (0.29~1.21%) 42
B. H. Kim et al.: Pharmacokinetic characteristics of bepotastine besilate in healthy subjects 이었다. 투여량으로표준화한 AUC/D, C max/d는 10mg 용량군에서 39.71 ± 2.86 μg h/l/mg, 9.72 ± 2.27 μg/l/mg이었고, 20mg 용량군에서 38.84 ± 4.42 μg h/l/mg, 9.44 ± 1.52 μg/l/mg이었으며, T max 는 10mg, 20mg 용량군에서각각 1.00~1.03 h, 1.00~ 2.02 h 이었다 (Table 2). 그리고, 약동학적선형성을검증하기위해 AUC/D, C max/d, 그리고 CL/F, Vd/F, t 1/2 의용량군간차이를비교한결과통계적인차이는없었으며 (Table 3), 투여량에비례하여 AUC와 C max 가증가하는특성을선형회귀분석으로검증시, 베실산베포타스틴은시험용량의범위에서선형적약동학적특성을보였다 (AUC slope: 95% Confidence Interval (CI), 30.92~45.02, r 2 = 0.90; AUC intercept: 95% CI, -94.04~128.91; C max slope: 95% CI, 6.28~12.04, r 2 = 0.75: C max intercept: 95% CI, -39.91~51.09) (Figure 2). 임상연구기간동안총 16명의피험자중 1명의피험자에서맥립종 (hordeolum) 이발생하였다. 맥립종은마지막외래내원시발생하였으므로시험약과의인과관계는없다고평가하였다. 또한, 모든피험자에서임상실험실검사및활력징후, 심전도검사, 신체검사를평가한결과시험기간중임상적으로의미있는소견은관찰되지않았다. 고찰총 16명피험자에게베실산베포타스틴 10 mg과 20 mg을각각투여한결과투여량에비례하여 AUC와 C max 가비례적으로증가하는약동학적선형성을확인할수있었고, 임상실험실검사를비롯한각종안전성평가결과임상적으로의미있는소견은관찰되지않았다. 본연구에서는약동학적선형성고찰을위해투여량에대한 AUC 및 C max 의선형회귀분석을실시하였으나 7),8), 일부연구는선형성입증을위해로 그변환후회귀분석을실시하기도한다 9),10). 본연구에서도약동학적선형성고찰을위해로그변환투여량에대한로그변환 AUC 및로그변환 C max 의선형회귀분석을실시하였으며, 그결과 AUC, C max 기울기의 95% 신뢰구간이 0.82~1.11, 0.66~1.28로서모두 1을포함함을확인할수있었다. 따라서, 로그변환여부는약동학결과의선형성입증에영향을미치지않았다. 임상시험에참여한피험자의인구학적정보중체중은 20 mg 용량군에서다소작은경향을보였고용량군간통계적인차이를보였으나, 표준체중 20% 이내의표준체형으로서 10 mg 용량군의평균체중과비교시큰차이는아니라고판단하였다. 따라서체중의용량군간차이가약동학분석결과에미치는영향은작을것으로판단되었다. 본연구기간동안진정작용 (sedation) 을비롯한중추신경계관련유해사례는없었으며, 이는베실산베포타스틴이혈중에비해뇌로적게분포하였기때문으로생각된다. 이와관련하여최근동물실험에서베실산베포타스틴이뇌의뇌혈관장벽 (blood brain barrier) 에존재하는약물수송체인 P-glycoprotein 의기질 (substrate) 이며, P-glycoprotein 의작용으로인하여약물의뇌분포가제한되었다는결과가있다 11). 또한유사계열 non-sedating H 1 히스타민수용체길항제인 cetirizine, loratadine 그리고 desloratadine 의동물실험결과에서도 P-glycoprotein 유전자결핍생쥐는정상생쥐에비해 AUC ratio ( 뇌 / 혈장 ) 가상대적으로크게증가하였다는보고들이있다 12). 이는베실산베포스타틴이뇌혈관장벽을통과하는데에있어서 P-glycoprotein 의역할이중요하며사람에서도뇌로의분포가제한적일것이라는점을시사한다. 일본인비염환자에게베실산베포타스틴을투여한임상시험에따르면코막힘을비롯한비염증상개선율이 10 mg/ 일, 20 mg/ 일, 40 mg/ 일투여군에서각각 58.9%, 65.3% 및 64.4 % 로서세군간 43
김보형외 : 건강한한국인피험자에서베실산베포타스틴의약동학특성에대한연구 유의한차이는없었지만, 20 mg/ 일투여군에서가장높았으며모든용량군에서우수한내약성이관찰되었다 13). 그리고, 건강한사람에게 histamine을투여하여피부에 wheal-flare 반응을생성한후베실산베포타스틴 10 mg, 1일 2회투여하여피부반응의소실경향을확인한결과, 시간경과에따라피부반응이효과적으로호전됨을관찰할수있었다 14). 또한, 일본인비염환자에게베실산베포타스틴 10 mg, 2회 / 일, 4주간반복투여후내약성을평가한결과유해사례발생률은 5.9%(7/118) 이었고가장흔한유해사례는졸음, 구갈, 소화기증상등으로서우수한내약성을확인할수있었다 13). 따라서, 현재일본에서는알레르기성비염을비롯한만성두드러기, 피부질환에수반된소양증등에대해베실산베포타스틴 10 mg 1일 2회투약을권장하고있다 15). 건강한일본인을대상으로베실산베포타스틴 10 mg, 20 mg을투여후, 측정한 C max 는 101.3 μg/l, 199.5 μg/l이었고, AUC는 438.6 μg h/l, 879.7 μg h/l이었으며 t 1/2 는 2.4 h, 2.3 h로산출되어본연구결과와유사하였다 15). 또한, 체내흡수된약물은혈장및뇨중에대사체형태로는거의검출되지않았고투여후 24시간까지투여량의 75~90% 가미변화체 (unchanged form) 로신장을통해배설되었으며 15), 베실산베포타스틴 10 mg 투약 1시간및 2시간후혈장단백결합률은각각 55.9%, 55% 로보고되었다 15). 따라서, 베실산베포타스틴은혈장단백결합률이낮으므로민족간의차이또는단백결합률이높은병용약물을투여할경우에도혈장단백질로부터경쟁적치환으로인해임상적으로중요한상호작용이일어나는예는적을것으로예상되며이로인해유효성또는안전성에미치는영향도적을것으로판단된다. 한편, ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) E5 지침서는약물이다음과같은특성을만족할때 ethnically insensitive 하다고규정한다 ; 약동학적선형성, 최소한의대사, 높은생체이용률, 낮은단백결합률, 투여량증가에따른효능 (efficacy) 및안전성의 flat 한특성. 그리고이런조건들을만족하는약물의경우, 외국임상자료의국내적용이용이하다고설명한다 16). 또한, 식품의약품안전청 (KFDA) 은비교적넓은안전역을가지고있고, 약동-임상효과 / 안전성관계가잘정립되어있으며, 약동학적변화가임상적유효성또는안전성의변화를잘반영해주는약물의경우, 약동학임상시험으로도만족할만한가교자료를얻을수있다고설명한다 17). 앞서설명한일본인임상시험결과를살펴보면, 베실산베포타스틴의경우약물이거의대사되지않고신장으로제거된다는점, 혈장단백결합률이낮다는점, 투여량이증가해도내약성이우수하며약물의효과가 flat 한경향을보인다는점, 그리고본연구에서한국인과일본인약동학결과가유사하다는점을고려할때한국인환자에게도일본인환자와마찬가지로베실산베포타스틴 10 mg 1일 2회투약이적절한용법이라고판단된다. 요약하자면, 본임상연구결과를통해베실산베포타스틴은투여된 10~20 mg 용량범위내에서약동학적선형성을보였고안전성및내약성이우수한것으로판단되었으며, 한국인환자에게베실산베포타스틴 10 mg 1일 2회투약이치료에적절한용법이라고판단되었다. 참고문헌 1. Min KU, Kim YK, Jang YS, Jung JW, Bahn JW, Lee BJ, Kim HY, Lee SR, Son JW, Cho SH, Park HS, Lee MH, Kim YY. Prevalence of allergic rhinitis and its causative allergens in people in rural area of Cheju Island. J 44
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