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1 wz (010), 40«1y J. Kor. Pharm. Sci., Vol. 40, No. 1, 1-7 (010) 생물학적동등성시험을위한통계처리프로그램 (BioEquiv) 의개발 z 1 Áyù Á 3 Á 4 Á 1 1 û w m w, w wx, 3 û w w w, 4 û w w w ( Á Á ) Developmet of BioEquiv, a Computer Program for the Aalysis of Bioequivalece Saghoo Yoo 1, Na a Hwag, Yougchai Lim 3, YogBok Lee 4 ad Jeogsoo Park 1 1 Departmet of Statistics, Choam Natioal Uiversity Team of Uiversity-Idustry Cooperatio Program, Natioal Research Foudatio of Korea 3 Departmet of Pharmacology, Choam Natioal Uiversity Medical School 4 College of Pharmacy, Choam Natioal Uiversity (Received November 0, 009ÁRevised December 11, 009ÁAccepted Jauary 6, 010) ABSTRACT K-BEtest is a well kow program for bioequivalece test usig a desig. Lee et al.(1998) ad Park et al.(1999) suggested a 3 3 ad 3 desig, ad also discussed their beefits. We developed a computer program, called BioEquiv, which ca aalyze some complex experimetal desigs such as, 3 3 desig ad 3 desig icludig a stadard desig. This program is a user-friedly oe ad overcomes the disadvatages of K-BEtest. The detailed statistical formula ad structure of BioEquiv are preseted with some examples. The compariso betwee K-BEtest ad BioEquiv are give with actual data aalysis. BioEquiv is able to preset a table of ANOVA test over some complex experimetal desigs. Moreover K-BEtest ad BioEquiv draw the same result whe data cosists of desig. Key words Bioeqivalece, Computer program, Desig of experimets, Statistical test t (iovator drug) t(geeric drug).» t z xƒ š w w, t z swwš px yƒ z q t. 1) ƒ t xƒ t z w» w w x(bioequivalece test) w wš. w x» w x w w ü x z ùkü yx m w w w» w x., w e z w w w x š w ³ z sƒ w ƒ. 1-3) w, q w w m w Tel : 06) , jspark@ju.ac.kr DOI : /KPS w ful v v w. SAS, SPSS, R m v w m w ù w x m w œ m v. w yw w v K-BEtest w. v 4) K-BEtest 00, K-BEtest 007,, x wš, ü š. ù K-BEtest 007 š., Fm y (p-value) w ƒ š, w ƒ wš, m w ü wwš w w.» v w w ƒ w ey w v BioEquiv w (v vp ). K-BEtest 007 ƒ w v w y w. BioEquiv m 1

2 w x w m v (BioEquiv) wš w wš w. š, w m t» ³. š w x 5) z (carryover effect)ƒ x k w. 생물학적동등성시험설계와분산분석 w w x w x (crossover desig) w. x vx ù R wš x T ù w 1 ( 1 ), x T wš R ù w ( ) w w (Table I). t w Table II. t w mw w. 4) x ijk d, k» i j vx (j=1,,) w d. Table II w (sum of ) œ. SS T = x ijk CF, CF = x ijk i = 1j = 1k = 1 1 SS S = -- x ijk i = 1j = 1 k = 1 i = 1j = 1k = 1 1 SS G = G i CF, G i = x ijk i = 1 1 SS P = W k CF, W k = x ijk k = 1 CF j = 1k = 1 1 SS D = ( T r + T t ) CF, T r = ( x 1j1 + x j ), T t = x 1j + x j1 j = 1 ( ) i = 1j = 1 j = 1 4 Table I Crossover Desig Collectig subjects() w x ƒ ƒ. w q» r sƒ w e yw s³e ƒ w w w. ƒ yw s³e (logµ T logµ R ) w ƒ. 1) H 0 : H 0 : Radom allocatio ( logµ T logµ R ) δ L or ( logµ T logµ R ) δ U δ L < ( logµ T logµ R ) <δ U Group Phase 1 Washout period RT ( 1 ) TR ( ) Ref. (µ R1 ) Test (µ T1 ) Phase Test (µ T ) Ref. (µ R )» µ T x s³, µ R s³ ùkü. δ L δ U w ww ùkü ³ q l AUC Cmax ww log 0.8, w 1.5 w. (logµ T logµ R ) 90% w w ww w ƒ kwš w zw š w. 3 3 w w x w z ƒ ƒw 3ƒ w x v š. wù 3 3 mw w z». 3 3 ww» Table II ANOVA Table for Crossover Desig Source of variatio Degree of freedom Sum of Mea F Iter subjects Sequece df G 1 SS G MS G =SS G /df G F G =MS G /MS S/G Subject/group df S/G (-1) SS S/G = SS S SS G MS S/G =SS S/G /df S/G F S/G =MS S/G /MS R Itra subjects Period df P 1 SS P MS P =SS P /df P F P =MS P /MS R Drugs df D 1 SS D MS D =SS D /df D F D =MS D /MS R Residual df R (-1) SS R =SS T SS S SS D SS P MS R =SS R /df R Total df T 4-1 SS T J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

záyù Á Á Á 3 Table III 3 3 Crossover Desig Period Group Subjects Phase 1 Phase Phase 3 1 1 Referece Test1 Test +1 Test Referece Test1 3 +1 3 Test 1 Test Referece Table IV 3 Crossover Desig Period

6,9,10) 3 w w x 3 3 ³x (balaced complete crossover desig) š deƒ ¼ ³x (balaced icomplete block desig) 3 š. ù 7,8) 3 z ƒ š x z w š. z x y w» x w { z ƒ ùk ù xw k w. 3 ww» t ùkü Table IV. 3 t ³ x š w.

3 záyù Á Á Á 3 Table III 3 3 Crossover Desig Period Group Subjects Phase 1 Phase Phase Referece Test1 Test +1 Test Referece Test Test 1 Test Referece Table IV 3 Crossover Desig Period Group Subjects Phase 1 Phase 1 1 Referece Test1 +1 Test Referece Test 1 Test t ùkü Table III. w q» ƒ ƒƒ x s³ ù ƒ w w w. w ƒ t ù, ³ x š w. 6,9,10) 3 w w x 3 3 ³x (balaced complete crossover desig) š deƒ ¼ ³x (balaced icomplete block desig) 3 š. ù 7,8) 3 z ƒ š x z w š. z x y w» x w { z ƒ ùk ù xw k w. 3 ww» t ùkü Table IV. 3 t ³ x š w. 9,10) z m q w z w F m (F D ) y t v. w v BioEquiv Visual Basic 6.0 w. j w š v. 1 : v w Figure 1 x kw y ù.» v w x w. x kw k mw kw. : x kw v w w., j y, q mw. w x v w AUC, Cmax, Tmax k kw w. w j w v w w (Figure ). 3 : óù j w ù w p j w w Figure 1 Model structure optio of BioEquiv. 프로그램의개발및수행양식 r w w x w Figure The framework of BioEquiv. J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

4 4 w x w m v (BioEquiv) Figure 3 A result of aalysis from BioEquiv. y w. Figure 3 š p mw l p q, w. w ƒ» p mw w w., Tmax ³ y w š w w w w. 사례를통한기존프로그램과비교 4 w x w, x w w xwš. e x k x w ƒ w z, x mw AUC w (Table V). 5) «w K-BEtest 007 BioEquiv v w. K- BEtest 007 ƒ w r. K-BEtest 007 l w z LogTras p j w Table V A Example Data for Aalysis of Crossover Desig Phase Subjects Referece Test Phase Subjects Test Referece 1 A B A B A B A B A B A B A B A B A B A B A B A B J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

záyù Á Á Á 5 AUC w k š w. l w š w l p q xk ƒ w. w mw w x m. Figure 4 The result of aalysis usig K-BEtest 007. Calculatio p (Figure 4) l p.»ws³ 154.743 š x»ws³ 150.988, 1»»ws³ 154.904,»»ws³ 150.831.

5 záyù Á Á Á 5 AUC w k š w. l w š w l p q xk ƒ w. w mw w x m. Figure 4 The result of aalysis usig K-BEtest 007. Calculatio p (Figure 4) l p.»ws³ š x»ws³ , 1»»ws³ ,»»ws³ t Fm (F G ) 0.046, vx / Fm (F S/G ).879,» Fm (F P ) 0.6, Fm (F D ) 0.19 y w. w, w, y w š Fm ƒ Fm»ƒ w»ƒ Fm w w rw.»ws³ w 90% (0.8863, 1.074) KFDA w 90% t AUC w k š w. w š w l p wì q. BioEquiv w BioEquiv w w K-BEtest 007 ƒ x,, 1»,»»ws³ y w (Figure 3). w y z s³, t r y w. t, w, s³ w, Fm, y y w. K-BETest w. w vx,, vx /,»,,, w¾ w». y z 90% (log0.8) 0.314(log1.5) (-0.11, 0.07) w k š w. w K-BEtest 007 ƒ»ws³ w 90% (0.886, 1.074) KFDA w 90% t 3 3 3» 1 ƒ 1z w z x w 3 3 x w t Table VI Table VII. 6) BioEquiv mw w Table VIII Table VII w w s³ w w F m š. BioEquiv Table VII Table VIII w s³ w ƒ r» w SAS v w w w. SAS v BioEquiv w Table VI A Example Data for Aalysis of 3 3 Crossover Desig Group Subject Period A1 Ref Test Test A A A A A A B1 Test 1153 Ref Test B B B B B B C1 Test Test Ref C C C C C C J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

6 6 w x w m v (BioEquiv) Table VII ANOVA Table for 3 3 Crossover Desig Give by Lee 6) Source of variatio Iter subjects Degree of freedom Sum of w. w s³ w ƒ ƒ. BioEquiv SAS v w w w š w. Table VII y w v. BioEquiv t m wì y w ƒ ƒ w j. 결과및고찰 Mea Sequece Subject/group * Itra subjects Period * Drugs Residual *: p<.05 Table VIII ANOVA Table for 3 3 Crossover Desig Usig BioEquiv Source of variatio Iter subjects Degree of freedom Sum of Mea Sequece Subject/group Itra subjects Period Drugs Residual sƒw w x ( x), z w w š. k w» y w, w m w w m sƒ w š. m q w F F P v w. w d w wì w j» w. 11),1) w x» w m x, w. w 3 3 w y k 3 3 w m x wš mw ful w w BioEquiv w. v w» w mw» ü v w w.» v K-BEtest 007 w BioEquiv š., x k ƒ w w, w x w., w t w, w, s³ w, F m y w w w ƒ w., v w x» ü w w. wz w w w w x» m, z, t T y g v y. 4, 4 4 w ƒ w v j v txw ƒ w v w. w, x k w vx ƒ ww d. š š, m w. wz d š w, d wš w d m wš w ù. ù ƒ w (populatio bioequivalece; PBE) w (idividual bioequivalece; IBE) w v jš w. 13,14) ü BioEquiv w w x w r w yw w ¼» w. 감사의말씀 008 û w w w. J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

7 záyù Á Á Á 7 참고문헌 1) t t š 008-y, w x» ( ). ) C.M. Metzler, Bioavailability : A problem i equivalece, Biometrics, 30(), (1974). 3) y,,, w x, w, (1997). 4) Y.J. Lee, J.H. Choi, S.H. Sog, C.H. Seo, D.S. Kim, I.S. Park, K.H. Choi, H.K. Na, S.J. Chug, M.H. Lee ad C.K. Shim, Developmet of K-BEtest, a computer program for the aalysis of bioequivalece, J. Kor. Pharm. Sci., 8(4), 3-9 (1998). 5) «Ÿ, ½, ½, ½, ³, y»,, y,, w w,, (006). 6) Y.J. Lee, M.G. Lee, S.J. Chug, M.H. Lee ad C.K. Shim, Statistical aalysis of three sequece-three periods bioequivalece study : applicatio to bioequivalece test of odasetro formulatios, J. Kor. Pharm. Sci., 8(1), 35-4 (1998). 7) W.J. Westlake, The desig ad aalysis of comparative blood-level trials, Curret Cocepts i the Pharmaceutical Scieces, J. Swarbrick(Ed.), Lea & Febiger, Philadelphia (1973). 8) W.J. Westlake, The use of balaced icomplete block desigs i comparative bioavailability trials, Biometrics, 30(), (1974). 9) H.S. Oh, S.G. Ko, J.I. Kim ad S.G. Park, Assessig bioequivalece with two ew drug formulatios ad a referece formulatio, Korea J. Applied Statist., 1(1), (1999). 10) S.G. Park, J.I. Kim, S.S. Chae, S.G. Ko, H.S. Oh, W.Y. Yag, D.S. Kim ad Y.W. Choi, Statistical aalysis of bioequivalece study i 3 crossover desig, J. Kor. Pharm. Sci., 8(4), (1998). 11) A.L. Heaff, B. Giraudeau, G. Baro ad P. Ravaud, Quality of Reportig of Noiferiority ad Equivalece Radomized Trials, J. Am. Med. Assoc., 95, (006). 1) S. Rai ad A. Pargal, Bioequivalece: A overview of statistical cocepts, Idia J Pharmacol., 36(4), (004). 13) V.W. Steiijas, Some coceptual issues i the evaluatio of average, populatio, ad idividual bioequivalece, Drug Iformatio Joural, 35, (001). 14) S.-C. Chow, J. Shao ad H. Wag, Statistical tests for populatio bioequivalece, Statistica Siica, 13, (003). J. Kor. Pharm. Sci., Vol. 40, No. 1(010)

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16(1)-3(국문)(p.40-45).fm w wz 16«1y Kor. J. Clin. Pharm., Vol. 16, No. 1. 2006 x w$btf3fqpsu'psn û w m w Department of Statistics, Chonnam National University Eunsik Park College of Natural Sciences, Chonnam National University