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 (009 11 0 Á09 1 11 Á010 1 6 ) 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)530-3445, E-mail : jspark@ju.ac.kr DOI : 10.4333/KPS.010.40.1.001 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 3 3 3 w ƒ w ey w v BioEquiv w (v vp ). K-BEtest 007 ƒ w v w y w. BioEquiv m 1
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 Group Subjects Phase 1 Phase 1 1 Referece Test1 +1 Test Referece 3 +1 3 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) 3 3 3 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 3 3 3 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 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 A1 161.689 135.4969 B1 134.0433 19.0101 1 A 165.9853 117.568 B 111.8941 105.7444 1 A3 179.045 16.6813 B3 148.9855 114.0035 1 A4 108.0077 150.5415 B4 14.4313 14.536 1 A5 171.3697 10.3956 B5 106.7475 74.04033 1 A6 137.7517 166.8764 B6 167.0134 65.3345 1 A7 15.5794 119.509 B7 15.09 188.4959 1 A8 10.7407 133.405 B8 3.3459 18.371 1 A9 135.01 113.1984 B9 17.937 08.7764 1 A10 166.033 13.1405 B10 144.615 154.3335 1 A11 169.8666 11.5633 B11 135.816 1.14 1 A1 158.8739 10.987 B1 18.49 05.0079 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. 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% 0.8 1.5 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% - 0.314(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% 0.8 1.5 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 1 3 1 A1 Ref. 1176 Test 1 1144 Test 14319 A 10913 1114 11640 A3 11004 1180 1134 A4 14377 153 13700 A5 15110 18308 18598 A6 1644 3917 4176 A7 11367 1054 134 B1 Test 1153 Ref. 9771 Test 1 1794 B 1411 19 18396 B3 6339 7860 7907 B4 006 17667 353 B5 1306 17170 15114 B6 1913 1547 17058 B7 0043 15816 19540 3 C1 Test 1 861 Test 11015 Ref. 9030 C 16785 15493 19305 C3 14847 13936 1399 C4 669 6938 7677 C5 11060 13337 1348 C6 13196 11538 1685 C7 14008 1906 14744 J. Kor. Pharm. Sci., Vol. 40, No. 1(010)
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 88374808 44187404 0.904 Subject/group 18 8804115 489088.057* Itra subjects Period 1836856 918148 4.141* Drugs 11679744 583987.634 Residual 38 8451160 17135 *: 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 88374984 4418749 0.9 0.43 Subject/group 18 88041755 4890319.06 0.000 Itra subjects Period 18363547 9181773 4.14 0.04 Drugs 11680341 5840170.63 0.085 Residual 38 8449094 17081 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, 3 3 3 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)
záyù Á Á Á 7 참고문헌 1) t t š 008-y, w x» (008.5.7). ) C.M. Metzler, Bioavailability : A problem i equivalece, Biometrics, 30(), 309-317 (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(), 319-37 (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), 41-51 (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), 31-39 (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, 1147-1151 (006). 1) S. Rai ad A. Pargal, Bioequivalece: A overview of statistical cocepts, Idia J Pharmacol., 36(4), 09-16 (004). 13) V.W. Steiijas, Some coceptual issues i the evaluatio of average, populatio, ad idividual bioequivalece, Drug Iformatio Joural, 35, 893-899 (001). 14) S.-C. Chow, J. Shao ad H. Wag, Statistical tests for populatio bioequivalece, Statistica Siica, 13, 539-554 (003). J. Kor. Pharm. Sci., Vol. 40, No. 1(010)