Interspecies Pharmacokinetic Scaling and the Prediction of Human Pharmacokinetics Using Animal and Cell Models

摘要: The allometric scaling is an empirical method developed based on cross-species similarities in anatomy, physiology, and biochemistry, with a power function correlating physiological parameters body size (Y = aWb). This has been used successfully to describe number of anatomical properties applied the projection human pharmacokinetic (PK) for small-molecule drugs therapeutic proteins. However, most high variability hepatic metabolism, this may not work well extrapolation metabolic clearance from laboratory animals humans. To improve predictability humans, several modified methods using (i) maximum life span potential (MLP), (ii) brain weight (BRW), or (iii) liver blood flow (LBF) as correction factor, (iv) integration vitro data into by normalizing vivo factors have recommended tested. These improved accuracy prediction some extent are reviewed chapter. In recent years, there increasing interest physiologically (PBPK) cell-based (CBPK) modeling. Both approaches similar assumption that PK could be scaled up humans according fundamental principles. advanced allow input information different sources (e.g., physicochemical drug molecule, permeability binding affinity experiments, profiles animal tests clinical trials). addition clearance, volume distribution), PBPK CBPK models also predict concentration–time tissues associated efficacy and/or toxicity. utility modeling goes beyond “first-in-human trial,” it continuously updated new (physiological related). Some tools techniques employed discussed second half chapter. Keywords: interspecies scaling; prediction pharmacokinetics; binding subcellular components; cell-based model; modelling simulation