群體藥代動(dòng)力學(xué)及其應(yīng)用

1、)()70(1 ijViBWijExpBWVpopV群體群體亞群體亞群體i個(gè)體個(gè)體j群體群體亞群體亞群體個(gè)體個(gè)體)(1 BWBWiVpopVpopiBWX, VivKXo105)7071(05. 01 10012VpoptKeVXoCiktKiExpViXoiCik)70(1 ikiBWtKiExpBWVpopXoiCikijkijkijKijViijtExpKpopExpExpVpopXoCijk)()(ijkijkijKijViBWijtExpKpopExpExpBWVpopXoCijk)()()70(1 iktKiExpViXoiCik)65BW( )65(1 (BWiPpopPpopi

2、BW65/iBWBWPpopPpopi1 therwise , 1 0DDFoDSFMifDFFiPpopPpopiDFijPpopiPij)()()(ijExpPpopiPijijPpopiLnPijLnYpredYobs)1 ( YpredYobs2) 1 1 ( YpredYobs2)(iiiOLSYpredYobsOFV)(/)(2VariLnVariYpredYobsOFViiiELS )Ypred -(Yobs )Ypred -(Yobs Oii1TiiFV)()(P1PpopPPpopjTjijkijkijijijijkijkijktKExpVXoYpredC)(ijkijkjK

3、ijViBWijtExpKpopExpExpBWVpopXoCijk)()()70(1 )()70(1 )(ijViBWijijKiijExpBWVpopVExpKpopKPLLAIC2)2( )(iExpCLpopCLiCL)()1 ()DF1 (iExpMNFCCLpopCLiCL)()70(1 (2222/2/iViVGNDRiVBWiExpGNDRBWpopVV)(222iViExppopVVME (mean predicted error, ME) MSE (mean squared prediction error)RMSE (root mean squared predictio

4、n error)SPE (standardized prediction error, SPE)PREDOBS11ME(C-C)NNi2PREDOBS11MSE(C-C)NNi2PREDOBS11RMSE(C-C)NNiOBSPRED PREDC-CSPESDCNONMEMDose, Conc.,Patient InfoModel ValidationFinal Pop PK ModelCsA PopulationModel BuildingC-TDMDose Individualizationby Simulation以群體藥物動(dòng)力學(xué)方法建立以中國(guó)人群為對(duì)象的智能化環(huán)孢A數(shù)據(jù)庫,指導(dǎo)臨床合理

5、化用藥 對(duì)象: 成年腎移植病人 給藥: 100550 mg/日 采樣時(shí)間: C0, C2 模型化工具: NONMEMlBase ModellStatistical Model & Residual Random Effect ModellFixed Effect (Covariate) Model-K t-Ka t0Ka XC (e-e)(V/F) (Ka-K)ijTV jijP PExp()OBSPRED12C C (1 ) TVTVCOVRMEANiP P f (COVR - COVR )iTVTVCOVRiP P f COVRiCovariatesOFVP-valueCovari

6、atesOFVP-valueForward InclusionBackward EliminationPOD-366.320.001TBIL-71.9230.05HCT47.2390.001CBW-55.2260.05INHI52.9550.001Age-48.850.05Age57.1550.001INHI-55.5510.05CBW78.8480.001HCT-45.8380.05TBIL62.5570.001ALT-10.810.05POD134.260.05HGHT-2.4370.05ALP-2.4340.05GGT-1.2610.05DRUG-1.060.05i(Ka) =1.28

7、Exp( Kai) 1/hriiiiiii(CL/F)28.5 - 1.24 POD - 0.252 (TBIL - TBIL) 0.188 (CBW- CBW) - 0.191 (Age - Age) - 2.45 INHI - 0.212 (HCT - HCT) Exp( CLi) L/hri(V/F) =133 LInter-indv: CVCL = 19.7%CVKA = 179%Intra-indv: Prop = 30.8%Addt = 42.4 ng/mLOBS vs. PRED & IPREDWRES vs. PRED, TIME & IDNONMEM法與刀切法

8、計(jì)算結(jié)果的比較法與刀切法計(jì)算結(jié)果的比較 NONMEM estimate Jackknife estimateParameterEstimateSE95% C.I.EstimateSE95% C.I.CL/FTV (L/h)28.50.93226.7 -30.328.50.84926.6-30.4V/FTV (L)1335.36122 - 1441342.848127-140fPOD 1.240.210.830 - 1.651.290.1590.926-1.644fTBIL0.2520.0430.168 - 0.3360.3060.0350.226-0.386fCBW0.1880.0350.11

9、9 - 0.2570.2170.0410.124-0.309fAge0.1910.0330.126 - 0.2560.1580.0330.082-0.233fINHI2.450.6661.14 - 3.762.80.4111.87-3.73fHCT0.2120.0410.132 - 0.2920.220.0490.108-0.332模型驗(yàn)證（內(nèi)部）基礎(chǔ)模型與最終模型預(yù)測(cè)誤差的比較Base modelFinal modelME (ng/mL) (95%C.I.)-5.5-2.2(-21.8 10.8)(-17.4 12.84)MSE (ng/mL)22735923387 (95%C.I.)(22

10、408 32310)(18820 27953)RMSE (ng/mL) (95%C.I.)115.1101.1(103.5 126.9)(89.7 112.4)SPE Value (95%C.I.)-0.05 (-0.04 - 0.14) S.D.-0.97模型驗(yàn)證（外部）模型仿真模型仿真?zhèn)€體化給藥個(gè)體化給藥通過軟件C-TDM進(jìn)行給藥個(gè)體化Covariant InfoTest Dose12 ObservationsIndividual ParametersSimulated Individual Concentration w/ 90% C.I.C-TDMSuggested Individua

11、lized DoseTherapeutical WindowPopulation PK Modeling with NONMEM查找添加刪除修改預(yù)測(cè)校正結(jié)果打印報(bào)告腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的基本功能塊1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥

12、情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告數(shù)據(jù)庫和群體藥物動(dòng)力學(xué)相結(jié)合最緊密的功能將群體藥物動(dòng)力學(xué)研究結(jié)果應(yīng)用于實(shí)際的重要方式對(duì)于臨床應(yīng)用具有相

13、當(dāng)?shù)膽?yīng)用價(jià)值預(yù)測(cè)群體藥物動(dòng)力學(xué)模型：Cl = TVCl+ age_Cl (agei- agemedian) exp(Cl)V = TVV+ WT_V (WTi- WTmedian) exp(V)ka = TVka+ sex_Cl sexi exp(ka)C = f (t ; Cl, V, ka) (1 + p) + aCl N(0, Cl2), V N(0, V2), ka N(0, ka2)p N(0, p2), a N(0, a2)預(yù)測(cè)群體預(yù)測(cè)ClpopVpopkapop= TVCl= TVV= TVkaCpop= f (t ; Clpop, Vpop, kapop)預(yù)測(cè)亞群體預(yù)測(cè)獲得，信

14、息ageiWTisexiClsubVsubkasub= TVCl+ age_Cl (agei- agemedian)= TVV+ WT_V (WTi- WTmedian)= TVka+ sex_Cl sexiCsub= f (t ; Clsub, Vsub, kasub)預(yù)測(cè)個(gè)體預(yù)測(cè)除，信息外，還需要ageiWTisexi藥物濃度ClindiVindikaindi= TVCl+ age_Cl (agei- agemedian) exp(Cl)= TVV+ WT_V (WTi- WTmedian) exp(V)= TVka+ sex_Cl sexi exp(ka)Cindi= f (t ; Cl

15、indi, Vindi, kaindi)擬合得到，ClVkaCl = TVCl+ age_Cl (agei- agemedian) exp(Cl)V = TVV+ WT_V (WTi- WTmedian) exp(V)ka = TVka+ sex_Cl sexi exp(ka)預(yù)測(cè)TVClTVVTVka群體預(yù)測(cè)群體預(yù)測(cè)亞群體預(yù)測(cè)亞群體預(yù)測(cè)個(gè)體預(yù)測(cè)個(gè)體預(yù)測(cè)TVCl+ age_Cl (agei- agemedian)TVV+ WT_V (WTi- WTmedian)TVka+ sex_Cl sexiTVCl+ age_Cl (agei- agemedian) exp(Cl)TVV+ WT_V (W

16、Ti- WTmedian) exp(V)TVka+ sex_Cl sexi exp(ka)第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)告第一部分 腎移植術(shù)后患者環(huán)孢霉素A用藥情況數(shù)據(jù)庫系列軟件的開發(fā)1.查看2.查找3.添加4.修改5.刪除6.預(yù)測(cè)7.校正結(jié)果8.打印報(bào)表應(yīng)用舉例Model 302: Before BW adjustment for V1Model 312: After BW adjustment for V1Population Pharmacokinetic/ Pharmacodynami

17、c Studies of Prodrug AQ0.010.11101001000020406080100120140160Time (min)Conc. (uM) .-4000400800120016002000Infusion Rate (umol/min)AQPR from AQPR from DIPAQ IV RateDIP IV Rate0.010.11101001000036072010801440Time (min)Conc. (uM) .AQPR from AQPR from DIPPart I: Population PK ModelingPR and Its ProdrugS

18、low Balance ModelX1, V1X2, V2X3, V3CL1CL2CL3X10,V10X20,V20X30,V30CL10CL20CL30IV AQX1, V1X2, V2X3, V3CL1CL2CL3IV PRProdrugDIPFm CL10 / (1-Fb1) / V10X0 Fb1,Fb2,Fb3 Final PK Model (K701)FCL1CL2CL3V1V2V3FB1FB2FB3CL1_ageL/minL/minL/minLLLPopulation0.4360.0483 0.01274.641.251.59S.E.0.0210.0120 0.00390.300

19、.270.26ETA0.0276S.E.0.0114EPSILON0.0354S.E.0.0108Population0.5831.772.390.97916.442.93950.01860.9110.2410.0371S.E.0.0280.100.590.1193.66.7410.00120.0430.1080.0045ETA0.05320.165S.E.0.04040.192EPSILON0.0792S.E.0.0051AQ PR (from AQ or DIP)1.28(0371.077.11AgeCLAQ)019.01(11AQDIPCLCL)91.01(22AQDIPCLCL)24.

20、01(33AQDIPCLCLPart II: Population PK/PD Modeling1. Continuous Data (BIS)X1, V1X2, V2X3, V3CL1CL2CL3XE, V1KeoEffectKeo)(111EEEXXVKeodtVdXdtdC)(max50EECECCEEoEffectEffectORIGINAL BIS DATAiv AQiv DIP020406080100120-252575125Time (min)BIS (%)DIP 13 (177 mg)Sampling Point0204060801001200.1110100PR (uM)BI

21、S (%)DIP 13 (177 mg)020406080100120-252575125Time (min)BIS (%)AQV 13 (1580 mg)Sampling Point0204060801001200.1110100PR (uM)BIS (%)AQV 13 (1580 mg)Estimated PD ParametersKeoEoEmaxEC50Gamma1/min%uMPopulation26.84.1095.915.51.93S.E.4.50.370.40.80.09ETA0.2890.345S.E.0.1220.107EPSILON0.296S.E.0.030Popula

22、tion0.09304.2195.815.32.05S.E.0.01610.520.55.471.17ETA0.1660.110S.E.0.1080.047EPSILON0.359S.E.0.058PR (AQ)PR (DIP)93. 193. 193. 15 .159 .9510. 4(%)EEAQCCBIS05. 205. 205. 23 .158 .9521. 4(%)EEDIPCCBIS0123456010203040Conc.OAASPart II: Population PK/PD Modeling2. Categorical Data (OAAS)OAAS PD Paramete

23、rs (DIP) Ke01/minPopulation1.35-22.91.353.918.150.160S.E.0.212.40.400.570.810.010ETA0.04260.0472S.E.0.01110.0120)exp(1)exp()2(11EECCP)exp(1)exp()3(22EECCP)exp(1)exp()4(33EECCP)exp(1)exp()5(44EECCP)2() 1 ( PP)2() 3()2(PPP) 3()4() 3(PPP)4()5()4(PPP)5(1)5(PP)5(5)4(4) 3(3)2(2) 1 ()(PPPPPpredictedPLogistic Transform:OAAS PD Modeling (DIP)00.250.50.751010203040PR (uM)Probability0123456OAASTime (min)OAAS01020304050123456ID= 1Time (min)OAAS01020304050123456ID= 2Time (min)OAAS01020304050123456ID= 3Ti