Developing new methods for BE studies建立新的生物等效性研究方法Drugs with long half-livesT1/2DrugBlood sampling Wash-out(wks)(wks)(days)5021≥50Amiodarone73≥7Digitoxin19≥45Hydroxychloroquine 4584≥8Tamoxifen
Developing new methods for BE studies 建立新的生物等效性研究方法 Drug T1/2 (days) Blood sampling (wks) Wash-out (wks) Amiodarone 50 21 50 Digitoxin 7 3 7 Hydroxychloroquine 45 19 45 Tamoxifen 8 4 8 Drugs with long half-lives
Problems with the application of standardcross-over design to drugs with long T1/2 Extensive sampling time延暹的抽血时間 Long washout period延長的藥物清洗期Time dependent variability in dispositionparameters受試者消除参数可能随时間而化 Subject compliance to study protocol受者依徙性差Increased study costs試费用增加
Problems with the application of standard cross-over design to drugs with long T1/2 ◼ Extensive sampling time 延遲的抽血時間 ◼ Long washout period 延長的藥物清洗期 ◼ Time dependent variability in disposition parameters 受試者消除參數可能隨時間而變化 ◼ Subject compliance to study protocol 受試者依從性變差 ◼ Increased study costs 試驗費用增加
Experimental data froma BE studyof piroxicam (t1/2=48h)TestReferenceRatio90%CIT/R(T)(R)1.02157.0155.2AUC0-000.99-1.04144.0141.01.02AUCo-t0.99-1.05135.21.03AUC144138.30.99-1.06126.91.03AUC120130.20.99-1.06AUC961.03118.6115.50.99-1.0699.6AUC72101.71.020.99-1.0478.277.11.02AUC480.99-1.0446.046.01.01AUC240.99-1.0324.91.01AUC1225.40.99-1.03
Test (T) Reference (R) Ratio T/R 90%CI AUC0- AUC0-t AUC144 AUC120 AUC96 AUC72 AUC48 AUC24 AUC12 157.0 144.0 138.3 130.2 118.6 101.7 78.2 46.0 24.9 155.2 141.0 135.2 126.9 115.5 99.6 77.1 46.0 25.4 1.02 1.02 1.03 1.03 1.03 1.02 1.02 1.01 1.01 0.99-1.04 0.99-1.05 0.99-1.06 0.99-1.06 0.99-1.06 0.99-1.04 0.99-1.04 0.99-1.03 0.99-1.03 Experimental data from a BE study of piroxicam (t1/2=48h)
Simulation study (Monte-Carlo approach)F.D.KC(t)V.(K.-K C(t):drug concentration at time tF:the bioavailabilityD: drug doseV: volume of distribution Ka: first-order absorption rate constant Ke: first-order elimination rate constantIntra-subject CV of 30%, 10%, 10% for Ka, Ke and V
Simulation study (Monte-Carlo approach) ◼ C(t):drug concentration at time t ◼ F: the bioavailability ◼ D: drug dose ◼ V: volume of distribution ◼ Ka: first-order absorption rate constant ◼ Ke: first-order elimination rate constant ◼ Intra-subject CV of 30%, 10%, 10% for Ka, Ke and V. ( ) ( ) ( ) K t K t a e a e a e e V K K F D K C t − − − − =