《生物药剂学与药物动力学》课程教学资源（专家讲座）How to Expand Routine Bioequivalence Studies to Generate New Knowledge（PPT）

Bioequivalence and Beyond: How toExpand Routine Bioeguivalence StudiestoGenerate NewKnowledgeOphelia Q. P. Yin, Ph. DMoses S. S. Chow, Pharm. DSchool of PharmacyThe Chinese University of Hong Kong

Bioequivalence and Beyond: How to Expand Routine Bioequivalence Studies to Generate New Knowledge Ophelia Q. P. Yin, Ph. D Moses S. S. Chow, Pharm. D School of Pharmacy The Chinese University of Hong Kong

Objective目的To share our experience in bioequivalence (BE)studies交流生物等效性研究的經To discuss how to “transform"’ routine “BE" datato generate new hypotheses and knowledge讨如何将常规生物等效性敷据型，產生新的科研設想和知To initiate an idea of collaboration among ChineseBE centers建護并散動中國生物等效性研究中心之周的广泛合作

Objective 目的 ◼ To share our experience in bioequivalence (BE) studies 交流生物等效性研究的經驗 ◼ To discuss how to “transform” routine “BE” data to generate new hypotheses and knowledge 討論如何將常規生物等效性數据轉型, 產生新的科研設想和知識 ◼ To initiate an idea of collaboration among Chinese BE centers 建議并啟動中國生物等效性研究中心之間的廣泛合作

Bioequivalence (BE) and Generic Drugs仿制藥与生物等效性-28福268101204Time (h)

Bioequivalence (BE) and Generic Drugs 仿制藥与生物等效性 0 1 2 3 0 2 4 6 8 10 12 Time (h) Cp A B

Four aspects of generating newhypotheses and knowledgeDeveloping new pharmacokinetic models/methods建立新的藥物動力學模型和研究方法Linking pharmacokinetics to pharmacodynamics连接藥物動力厚与藥效動力學Linking pharmacokinetics to pharmacogenetics接藥物動力學与遗傅藥理學Determining intra-individual variability测定个体内异

Four aspects of generating new hypotheses and knowledge ◼ Developing new pharmacokinetic models/methods 建立新的藥物動力學模型和研究方法 ◼ Linking pharmacokinetics to pharmacodynamics 連接藥物動力學与藥效動力學 ◼ Linking pharmacokinetics to pharmacogenetics 連接藥物動力學与遺傳藥理學 ◼ Determining intra-individual variability 測定個体內變异

Developing new pharmacokinetic models建立新的藥物動力學模型Plasma concentration200curves manifested distinct180double-peaks160Famotidine-54%140Ranitidine- 50%120100Acetaminophen- 25%806040200031269

Developing new pharmacokinetic models 建立新的藥物動力學模型 0 20 40 60 80 100 120 140 160 180 200 0 3 6 9 12 ◼ Plasma concentration curves manifested distinct double-peaks Famotidine-54% Ranitidine- 50% Acetaminophen- 25%

Interdigestive Migrating Motility Complex(IMMC)Phase I:Absence of motor activityPhase II:Irregular contraction processPhase III:Rhythmic contractions of highamplitudePhase IV:Transitional period corresponding to areduction in intensity and frequencyof contractionsItohZet al (1982).Gastroenterology1982;82:694-700

Interdigestive Migrating Motility Complex (IMMC) Phase I: Absence of motor activity Phase II: Irregular contraction process Phase III: Rhythmic contractions of high amplitude Phase IV: Transitional period corresponding to a reduction in intensity and frequency of contractions Itoh Z et al (1982). Gastroenterology 1982; 82: 694-700

Modified two-portion absorption model雨部分吸收模型K (t≥T)XiK12KaXpGAK212K1K,(t≥T2)

Modified two-portion absorption model 兩部分吸收模型 X1 X2 GA Xc Xp K1 (tT1 ) K2 (tT2 ) Ka K10 K12 K21

SubiectA1aSubjectA220002000150015001000100050050000026264804810121012time (hour)time (hour)ee2000Subject A42000SubjectA3150015001000100050050000602481012024681012time (hour)time (hour)SubjectA6SubjectA5e20002000150015001000100050050000082610124602481012time (hour)time (hour)Curvefittingforranitidineconcentrationdatawithdoublepeaks

Curve fitting for ranitidine concentration data with double peaks Subject A3 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject A5 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject A4 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject A1 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject A6 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject A2 0 500 1000 1500 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml)

subject B2SubjectB120004000(u/6u)(/bu)20001000000261012:4.8024681012time (hour)time (hour)Subject B3Subject B46000(w/bu)3000(w/bu)200040002000100000060262410124812810time (hour)time (hour)SubjectB5Subject B62000(u/6u)-2000(/6u)1000100000026810124024681012time (hour)time (hour)Curve fittingforranitidine concentrationdata with apparent singlepeak

Subject B1 0 2000 4000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject B3 0 2000 4000 6000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject B4 0 1000 2000 3000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject B5 0 1000 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) Subject B6 0 1000 2000 0 2 4 6 8 10 12 time (hour) concentration (ng/ml) subject B2 0 1000 2000 0 2 4 6 8 10 12 t ime (hour) concentration (ng/ml) Curve fitting for ranitidine concentration data with apparent single peak

Comparisonof ranitidinePKparametersobtained bythe modified two-portion absorptionmodel andnon-compartmental analysisparameternon-compartmentalanalysismodifiedabsorptionmodelGroupA (n=6)Tmax1 (h)1.20±0.361.36±0.39Tmax2 (h)3.42 ±0.662.97 ± 0.64Cmax1 (μg-ml)0.58 ± 0.160.63 ± 0.191.07 ± 0.271.22±0.29Cmax2 (μg-ml)AUCo-o (μg·homl1)5.62 ± 1.235.62 ± 1.34CL/F (Lh-1)55.53 ±12.4056.17 ± 14.42GroupB(n=6)Tmax (h)1.90 ± 0.421.84 ± 0.54Cmax (μgoml)2.07±1.362.05±1.34AUCo-o (μg·homl-1)6.22±1.946.31± 1.92CL/F (Lh-")52.20±16.3351.50±16.35

Comparison of ranitidine PK parameters obtained by the modified two￾portion absorption model and non-compartmental analysis parameter non-compartmental analysis modified absorption model Group A (n=6) Tmax1 (h) 1.20  0.36 1.36  0.39 Tmax2 (h) 3.42  0.66 2.97  0.64 Cmax1 (g•ml) 0.58  0.16 0.63  0.19 Cmax2 (g•ml) 1.07  0.27 1.22  0.29 AUC0- (g•h•ml-1) 5.62  1.23 5.62  1.34 CL/F (L•h -1) 55.53  12.40 56.17  14.42 Group B (n=6) Tmax (h) 1.90  0.42 1.84  0.54 Cmax (g•ml) 2.07  1.36 2.05  1.34 AUC0- (g•h•ml-1) 6.22  1.94 6.31  1.92 CL/F (L•h -1) 52.20  16.33 51.50  16.35