Predicting human pharmacokinetics from preclinical data: absorption

Predicting the rate and extent of oral absorption of drugs in humans has been a challenging task for new drug researchers. This tutorial reviews in vitro and PBPK methods reported in the past decades that are widely applied to predicting oral absorption in humans. The physicochemical property and permeability (typically obtained using Caco-2 system) data is the first necessity to predict the extent of absorption from the gut lumen to the intestinal epithelium (F(a)). Intrinsic clearance measured using the human microsome or hepatocytes is also needed to predict the gut (F(g)) and hepatic (F(h)) bioavailability. However, there are many issues with the correction of the inter-laboratory variability, hepatic cell membrane permeability, CYP3A4 dependency, etc. The bioavailability is finally calculated as F = F(a) × F(g) × F(h). Although the rate of absorption differs by micro-environments and locations in the intestine, it may be simply represented by k(a). The k(a), the first-order absorption rate constant, is predicted from in vitro and in vivo data. However, human PK-predicting software based on these PBPK theories should be carefully used because there are many assumptions and variances. They include differences in laboratory methods, inter-laboratory variances, and theories behind the methods. Thus, the user's knowledge and experiences in PBPK and in vitro methods are necessary for proper human PK prediction.