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1 w wz 19«1y Kor. J. Clin. Pharm., Vol. 19, No w p 35 mg w m w Á½ Á Á Á y Á w œw w w ( Á Á ) Pharmacokinetic Comparison of Actonel and Risenel Tablet Containing Risedronate sodium in Healthy Volunteers Sung-Up Choi 1, Young-Il Kim 2, Young-Joon Park 1, Jong-Oh Lee 3, Jin-Ho Song 4 *, and Seong-Wan Cho 2 * 1 Sam-il Pharm. Co. Ltd, Bang-Bae, Seoul, 990-1, Korea, 2 Department of Pharmaceutical Engineering, Konyang University, Nonsan, Chungnam, , Korea, 3 Biomedieng, Seong-Nam, Gyeonggi, , Korea, 4 College of Medicine, Chung-Ang University, Seoul, , Korea (Received February 12, 2009Á Revised April 15, 2009ÁAccepted May 11, 2009) The aim of this study was to evaluate the pharmacokinetic parameters of two risedronate preparations. The clinical assessment was conducted on 46 healthy volunteers who received one tablet (Risedronate sodium 35 mg/tablet) in the fasting state, in a randomized balanced 2 2 cross-over study design. After dosing of one tablet containing 35 mg risedronate sodium, blood samples were collected serially for a period of 48 hours. Plasma was analyzed for risedronate by using LC/MS/MS assay method. The analysis system was validated in specificity, accuracy, precision, and linearity., (the area under the plasma concentration-time curve from the zero-time to 48 hr) was calculated through the trapezoidal rule. C max (maximum plasma drug concentration) were compiled from the plasma risedronate concentrationtime data of each volunteer. No significant sequence effect was found for the pharmacokinetic parameters indicating that the cross-over design was properly performed. The 90 % - Confidence intervals of the ratio and the C max were from log to log and log to log , respectively. These values were within the acceptable intervals between 0.80 and Therefore, this study demonstrated that no statistically significant difference was identified with respect to the rate and extent of absorption. Key words - Risedronate sodium, Pharmacokinetic parameters, LC/MS/MS, Actonel p (Risedroate sodium; 1-hydroxy-2-[3- pyridinyl] ethylidene bisphosphonic acid monosodium salt) p (alendronate) wì œ e w s s p Correspondence to : w œw ( ) û w 119 Tel: swcho@konyang.ac.kr y w w ( ) p 221 Tel: jinhos@cau.ac.kr (bisphosphonate) s z œ e, l œ e w FDA w 5mg e, e z 6 l z ƒ ùkùš y ƒ n w w p. z w ww VERT(vertebral efficacy with risedronate therapy) w p 5mg 3 n z ƒ 5.4 %, n ƒ 1.6 % ƒw 41 %, 39 % w. 1-3) p û (<1 %) ùküš, w š. e 30 23

2 24 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 œ wš, z w 2 š w. w,» w w ( ml) wì wš, z x» w 30 1 ù w «wš. 4-7) p 30 mg w n w w q l Cmax 5.1±4.8 ng/ml, AUC 21.3±19.1 ng/mláh, š Tmax 0.81±0.32 h š ƒ, 8-12) x p ELISA w ù, k w y š ) ü t, w w w risedronate w œwš w. 2 2 w ( ) v p g m ( ) w 46 1 (risedronate sodium, 35 mg/ ) n w, x š w x ü k ywš, LC/ MS/MS x w. ƒ vx x l l w x - š w ( ) šx (C max ) q l w m w š w w sƒw š w. x x w ( ) v- p g m ( y B009) w, x ( ) ( y ) w, ùp 35 mg w w. Risedronate sodium Assia Chemical Industries Ltd.( : Ramat Hovav, Emek Sara, Be er Sheva, Israel) š yƒ w. x p w š, HPLC grade w. vx» vx w x œš y»,,, x,, ü x y x k wš w 50 w. 50 w w w ( w xz y 0529y) x w x (WBC, RBC, Hb, HCT, PLT, WBC Diff count), x yw (T.protein, Albumin, T.bilirubin, AST, ALT, T.cholesterol, Glucose, Creatinine, BUN), (Color,, ph, Protein, Glucose, Ketone, Bilirubin, Blood, Leukocyte, RBC, WBC, Epith) y z (x,, ) d ü w. x x x vx , 2 25 ù. I» 1, 2 x ú n wš, II» n w, n ƒ 1 ( ùp 35 mg) 1z n w. x x z 6 vx w vx y wš xü, w w w z w œw. z 22 z l ú n z 4 ¾ g. n 12 l x ¾ vx w n jš,,, xanthine ww. z 10 vx e g. x 6 vx» g wš x w. vx k wš vx heparinlocked catheter ewš blank x ƒƒ 10 ml xw. vx w n 8 l x ƒ 1 ( ùp 35 mg) 240 ml wì n w. vx x š w 1 w. x x» ( 5.2 ) 8) m» 3 ( ƒ AUC 8 80 % w )»» š w 48 w š, x z w ³ ( e 12z, šx 2z x) w, n n z 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 48 13z w. x I.V. catheter û xq w» w 1 ml x ü š 10 ml x w vx y x» vacutainer. x z I.V. catheter w x š w» w xq w. x x 3,000 rpm 10 w z x w x š ¾ -70 o C w. w w w» w n 12 w k n z 4

3 w p 35 mg w m w 25 ¾ k g, n z 4 x e z w œw, n z 10 x e z w œw. 10 ew wš 6» w wš n z 24 x óù z w w z ƒ g. x ú vx w wš n z 48 x wš w x,,»k y wš, vx II» x w ¾ ù w w w k z ƒ g. II» n x I» vx x m w w ³ 1z» w.»» x Risedronate» LC/MS/MS 14-15) w w ü t Zoledronate disodium tetrahydrate w. LC Pump NANOSPACE SI (Shiseido), autosampler NANOSPACE SI (Shiseido),» API5000 (Applied biosystems/mds SCIEX) w e ODP2 HP-4D ( mm, 5 µm, Shodex), Acetonitrile : 50 mm ammonium formate (ph 2.5) = 90 : 10 (v/v), 1.0 ml/min, 3 µl. x x ü p» š x w 14-15), k w y jš, LC/MS/MS w. Risedronate sodium t t water risedronate 1mg/mL z þ jš, þ w blank x w risedronate x ƒ ƒƒ 0.2 ( w ), 0.5, 1, 5, 10, 50 ng/ml ƒ t x. ƒƒ t x 1mL ü t water zoledronate (10 µg/ml) 50 µl š 10 mm ammonium bicarbonate 4 ml wì 1mL water equilibrate Bond Elut DEA cartridge loadingw water, methanol ƒƒ 1mL washing w z diazomethane solution 0.4 ml ƒw y g. z methanol 1 ml elutionwš» 55 o C w k 150 µl 50% acetonitrile ƒw w z 3µL w LC/MS/MS w.» j m l ü t vj w risedronate vj w (calibration curve) w. Fig. 1. The mass spectrum of Risedronate (precursor ion (A), product ion (B)).

4 26 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 w x 5 ww ü x (intra-day) wš w 5 x ww x (inter-day) w. d w z ƒ e QC d w e 15 % ü y wš vx l ƒ w» ¼ z -70 o C w x ew z 5 k w, x 1mL w» ü t zoledronate (10 µg/ml) 50 µl ƒw z w w LC/MS/MS w. j m l ü t vj w risedronate vj w, w l x risedronate w. w sƒ x sƒ w w e x - š w ( ), š x (C max ) w š x (T max ) š w. T max w x sƒw ye m v (K-BE test 2002, ver ) w α( )=0.05 (ANOVA) w. p y MS/MS spectrometry Risedronate ü t zoledronate precursor ion positive ion mode [M+H] +, risedronate m/z (Fig. 1), ü t m/z ion precursor ion w (Fig. 2). w precursor ion l ƒ product ion collision energy w scan w risedronate 25 ev m/z ion, ü t 41 ev m/z ion ƒ y w ƒƒ CID (collision-induced dissociation) z l w product ion w. p w LC/MS/MS w risedronate vj 2.3, ü t vj 3.2 š, risedronate ü t k yw. Risedronate ü t vj w ùkù (Fig. 3-4). 0.2 ( w ), 0.5, 1, 5, ng/ Fig. 2. The mass spectrum of Internal standard (zoledronate) (precursor ion (A), product ion (B)).

건강한 지원자에 있어서 리세드로네이트 35 mg 함유 악토넬정과 리세넬정의 약물 동력학적 비교 27 Fig. 3. The chromatogram of zero blank (A) and blank with Internal standard(i.s) (B). Fig. 4. The blank chromatogram of Risedronate 0.

2-50 ng/ml 범위 에서 양호한 직선성을 나타내었다. 정밀성, 정확성 및 감도 정밀성 및 정확성의 경우 0.2 (정량한계 농도), 0.5, 5 및 40 ng/ml의 4 가지 농도의 risedronate 혈장 표준액을 상기의 검체처리방법으로 처리하여 분석하였다.

5 건강한 지원자에 있어서 리세드로네이트 35 mg 함유 악토넬정과 리세넬정의 약물 동력학적 비교 27 Fig. 3. The chromatogram of zero blank (A) and blank with Internal standard(i.s) (B). Fig. 4. The blank chromatogram of Risedronate 0.2 ng/ml (LLOQ) and blank chromatogram with Internal standard(i.s) ml 농도의 표준액을 LC/MS/MS 로 분석하였을 때, 혈장시료 로부터 구한 risedronate의 검량선의 계산식은 y = x (R2 = , 1/X2 weighting)으로 ng/ml 범위 에서 양호한 직선성을 나타내었다. 정밀성, 정확성 및 감도 정밀성 및 정확성의 경우 0.2 (정량한계 농도), 0.5, 5 및 40 ng/ml의 4 가지 농도의 risedronate 혈장 표준액을 상기의 검체처리방법으로 처리하여 분석하였다. 정밀성은 risedronate 와 내부표준물질의 피크면적비의 표준편차를 risedronate와 내부표준물질의 피크면적비의 평균값으로 나눈 비의 백분율 (%)로서 구하였다. 하루에 5번 시행하여 일내 정밀성 (CV %로 표시)을 구하였고 5일간 실험을 반복 시행하여 일간 정 밀성 (CV %로 표시)을 구하였으며 정확성은 검량선에 의하 Table 1. Intra-day and inter-day precison and accuracy for the determination of risedronate in plasma. Precision (CV %) Concentration Intraday Interday (ng/ml) (n=5) (n=5) Accuracy (%) Intraday Interday (n=5) (n=5) 여 정량한 농도의 평균값을 기지의 농도로 나눈 비의 백분 율(%)로서 구하였다 (Table 1). 감도(최저정량한계) 크로마토 그램상에서 신호대 잡음비 (S/N ratio)를 5 이상으로 하고 정 밀성이 20 % 이하이고, 정확성이 80~120%인 조건을 만족

6 28 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Fig. 5. The plasma concentration of risedronate versus time curves after oral administration of the two risedronate preparations in korean volunteers. Mean values (± S.D.) for each formulations were represented on the graph (ø : Actonel tablet, ù : Risenel tablet; n=46, mean±sd) w w 0.2 ng/ml w. CV % ü %, % š, w (0.2 ng/ml) ü %, %. ü y 98.12~101.45%, y % š, w ü y %, y %. l x risedronate w LC/MS/MS w x w p,, y š y w. ƒ vx x p q k vx 50 vx A5 vx B22 I» x ƒƒ {m m y w w z ù x w x w. vx B13 I» x ù II» x w vx B25 I» x x w ù II» x w x m e sw j. 4 w 46 ƒ vx m n w z ƒ vx s³ x - š Fig. 5. ƒ vx n z 48 ¾ ƒ vx x - š l BA-Calc 2007 v w w. C max ƒ vx x - š l ƒ x w, T max ƒ vx x - š l š x w w. ƒ vx q k w Table 4. x m x w sƒ w w e x - š l w x ¾ x š w ( ), š x (C max ) w š x (T max ) š w. 1 24, 2 22, 46, T max w x sƒw ye m v (K-BE Test 2007) w w z w š x yw s³e 90 % w. x - š w ( ) šx (C max ) w ƒ vx yw C max w t m ƒƒ Table 2 Table 3 ùkü Table 2. Statistical results of bioequivalence evaluation in and C max between two risedronate tablets. ANOVA F-value F table Group or Sequence Subjects/Group Period Drug C max Group or Sequence Subjects/Group Period Drug

7 w p 35 mg w m w 29 Table 3. Lower and upper limit of 90 % confidence interval in and C max. Point estimation 90 % Confidence interval Lower limit Upper limit C max m z F F table w ù z y ƒ ùkûš, ü» z (period effect) ùk þ ù, (drug effect) ùkü (Table 2). x yw s³e 90% log log Table 4. Pharmacokinetic parameters after administration of two risedronate formulations in the bioequivalence study (, C max, T max ) (ng h/ml) AUC ƒ (ng h/ml) h j Vh j (%) C max (ng/ml) T max (h) T 1/2 (h) reference test reference test reference test reference test reference test reference test A A A A A A A A A A A A A A A A A A A A A A A A A B B B B B B B

8 30 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 4. Pharmacokinetic parameters after administration of two risedronate formulations in the bioequivalence study (, C max, T max ) (continued) B B B B B B B B B B B B B B B B B B Mean S.D š x yw C max s³e 90% log log log 0.8 log 1.25 ü w» ƒƒ w (Table 3). sƒw C max w w. š 35 mg v- p g m 35 mg w w w q w m v w ww, q l 2 w (, C max ) w x yw s³e 90 % log log š C max x yw s³e 90 % log log log 0.8 log 1.25 ü ùkû. w q. š x 1. Shin DH. Bisphosphonate. J Korean Acad Fam Med. 2006; 27(11): Suppl. November Dunn CJ, Goa KL. Risedronate: a review of its pharmacolo gical properties and clinical use in resorptive bone disease. Drugs 2001; 61(5): Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab. 1998; 83(2): Bekker P, Licata A, Harris S. Risedronate dose response in prevention of early postmenopausal bone loss. J Bone Miner Res. 1996; 11(3): S Singer FR, Clemens TL, Eusebio RA, et al. Risedronate, a highly effective oral agent in the treatment of patients with severe Paget 's disease. J Clin Endocrinol Metab. 1998; 83(6): Delmas PD, Balena R, Confravreux E. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997; 15(3): Reid D, Cohen S, Pack S, et al. Risedronate reduces the incidence of vertebral fractures in patients on chronic

9 w p 35 mg w m w 31 corticosteroid therapy. Arthritis Rheum. 1998; 41(1): S Fogelman I, Smith L, Mazess R, et al. Absorption of oral diphosphonate in normal subjects. Clin Endocrinol. 1986; 24(1): Mitchell DY, Eusebio RA, Dunlap LE, et al. Risedronate Gastrointestinal Absorption is independent of site and Rate of Administration. Pharm Res. 1998; 15(2): Mitchell DY, Heise MA, Pallone KA, et al. The effect of dosing regimen on the pharmacokinetics of risedronate. Br J Clin Pharmacol. 1999; 48(4): Lin J. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996; 18(2): Mitchell DY, Eusebio RA, Dunlap LE. Bioavailability administration of immediate-release and delayed-release risedronate formulations upon oral administration to healthy male subjects in fasted and fed state. Pharm Res 1996; 13: S Mitchell DY, Eusebio RA, Sacco-Gibson NA, et al. Doseproportional pharmacokinetics of risedronate on singledose oral administration to healthy volunteers. J Clin Pharmacol. 2000; 40(3): Zhu LS, Lapko VN, Lee JW, et al. A general approach for the quantitative analysis of bisphosphonates in human serum and urine by high-performance liquid chromatography/ tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006; 20(3): Mitchell DY, Eusebio RA, Pallone KA, et al. Single dose 27 Necciari J, Kiefer G, Maillard D. Pharmacokinetics of linearity of risedronate following oral administration of 2.5, (4-chlorophenyl) thiomethylene bisphosphonic acid after 5, or 30 mg to healthy volunteers. Pharm Res 1997; 14: S-609.

16(2)-3(p ).fm

16(2)-3(p ).fm w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No. 2. 2006 k v p w w sƒ B Á z C Á½ k B Á B Á B Á x B Á x D Á x C Á ³ C Á E B w w w C w w D ƒm w w w E œw Bioequivalence Study on Two Talniflumate Preparations