Estimating human drug oral absorption kinetics from Caco-2 permeability using an absorption-disposition model: Model development and evaluation and derivation of analytical solutions for k_a and F_a

Intestinal transcellular permeability (P_m), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorption-disposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k_a and F_a were deduced, and using Caco-2 permeability, F_a in humans was predicted for 51 structurally diverse compounds. Predicted F _a values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 ± 1.06% (-17 to 22%) and r² = 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k_a (k_a,eq) was found to be a key determinant of F_a, whereas under sink conditions, k_a is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P_m and k_a and between k_a,eq and F_a. This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination.