基于体外数据模拟和预测体内PK.pptxVIP

PK Simulation Prediction with IVIVE: ?In Vitro In Vivo Extrapolation; How to Predict PK with GastroPlus IVIVE approach;Why predict pharmacokinetics?;Methods to predict pharmacokinetics;Allometric scaling;IVIVE vs. Allometric scaling;Empirical method vs. PBPK:;Parameters describe PK profile ;* Modified from van de Waterbeemd, H, and Gifford, E. ADMET In Silico Modelling: Towards Prediction Paradise? Nat. Rev. Drug Disc. 2003, 2:192-204;ACAT Model;Absorption term in compartment number i: ASFtrans,I and ASFpara,i = transcellular and paracellular absorption scale factor in compartment i (nominal value is surface/volume, which is 2/Ri) Ri = radius of compartment i Ptrans,i and Ppara,i= transcellular and paracellular permeability  in compartment i* Vlum,i = volume of lumen for compartment i C(t)lum,i = lumen concentration in compartment i C(t)entU,i = unbound enterocyte concentration in compartment i C(t)pvU = unbound portal vein concentration ;Three primary properties of a drug/dosage form can limit absorption in the gastrointestinal tract: Solubility Dissolution rate Intestinal permeability GastroPlus? simulation ： Input data required would be preformulation information (solubility, permeability, pKa·····) Structure-property predictions (from ADMET Predictor?) provide estimates for: pKa, logP, solubility, permeability, etc. Accurate physiological situations are taken into consideration;Total amount dissolved;Structure-property predictions (from ADMET Predictor?) provide estimates for: pKa, logP, solubility, permeability, plasma protein binding, etc. Kp’s estimated from logP or logD and tissue properties ;Distribution;Clearance ;;Liver Metabolism Rate = CLh * Cliver CLh = Eh * Qh * RB Eh = CLinth* fu,plasma / [CLinth* fu,plasma + Qh * RB ] where CLinth = Σ Vmax(j) *Cu,hepat / (Km(j)+ Cu,hepat) Eh = total hepatic extraction Qh = hepatic blood flow rate RB = blood-to-plasma concentration ratio CLinth = total hepatic int