A permeability- and perfusion-based PBPK model for improved prediction of concentration-time profiles.

To improve predictions of concentration-time (C-t) profiles of drugs, a new physiologically based pharmacokinetic modeling framework (termed 'PermQ') has been developed. This model includes permeability into and out of capillaries, cell membranes, and intracellular lipids. New modeling components include (i) lumping of tissues into compartments based on both blood flow and capillary permeability, and (ii) parameterizing clearances in and out of membranes with apparent permeability and membrane partitioning values. Novel observations include the need for a shallow distribution compartment particularly for bases. C-t profiles were modeled for 24 drugs (7 acidic, 5 neutral, and 12 basic) using the same experimental inputs for three different models: Rodgers and Rowland (RR), a perfusion-limited membrane-based model (K p,mem ), and PermQ. K p,mem and PermQ can be directly compared since both models have identical tissue partition coefficient parameters. For the 24 molecules used for model development, errors in V ss and t 1/2 were reduced by 37% and 43%, respectively, with the PermQ model. Errors in C-t profiles were reduced (increased EOC) by 43%. The improvement was generally greater for bases than for acids and neutrals. Predictions were improved for all 3 models with the use of parameters optimized for the PermQ model. For five drugs in a test set, similar results were observed. These results suggest that prediction of C-t profiles can be improved by including capillary and cellular permeability components for all tissues.