A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins

摘要: The ability to predict subcutaneous (SC) absorption rate and tissue distribution of therapeutic proteins (TPs) using a bottom-up approach is highly desirable early in the drug development process prior clinical data being available. A whole-body physiologically based pharmacokinetic (PBPK) model, requiring only few parameters, plasma interstitial fluid concentrations TPs humans after intravenous dosing has been developed. Movement between vascular spaces was described by considering both convection diffusion processes 2-pore framework. model optimised variety literature sources, such as lymph/plasma concentration ratios animals, information on percentage dose absorbed following SC via lymph animals showing loss radiolabelled IgG from site humans. resultant used t max profiles for 12 (molecular weight 8–150 kDa) dosing. predicted were generally comparable observed data. within 3-fold reported values, with one third predictions 0.8–1.25-fold. There no systematic bias simulated C although general trend underprediction observed. No clear prediction accuracy TP isoelectric point or molecular size apparent. mechanistic PBPK here can be applied into blood movement target tissues