Abstract:
:Prediction of the rate and extent of drug absorption upon oral dosing needs models that capture the complexities of both the drug molecule and intestinal physiology. We report here the development of a continuous intestinal absorption model based on the convection-diffusion equation. The model includes explicit enterocyte apical membrane and intracellular lipid radial compartments along the length of the intestine. Physiologic functions along length x are built into the model and include velocity, diffusion, surface areas, and pH of the intestine. Also included are expression levels of the intestinal active uptake transporter OATP2B1 and efflux transporter P-gp. Oral dosing of solution as well as solid (with a dissolution function) was modeled for several drugs. The fraction absorbed (FA) and concentration-time (C-t) profiles were predicted and compared with clinical data. Overall, FA was well predicted upon oral (n = 21) or colonic dosing (n = 11), with four outliers. The overall accuracy (prediction of the correct bin) was 81% with outliers and 90% without outliers. Of the nine solution dosing data sets, six drugs were very well predicted with an exposure overlap coefficient (EOC) > 0.9 and predicted Cmax and Tmax values similar to those observed. Of the six solid dose formulations evaluated, the EOC values were > 0.9 for all drugs except budesonide. The observed precipitation of nifedipine at high doses was predicted by the model. Most of the poor predictions were for drugs that are known to be transporter substrates. As proof of concept, incorporating OATP2B1 and P-gp markedly improved the EOC and predicted Cmax and Tmax for fexofenadine. Finally, the continuous intestinal model accurately recapitulated the known relationships between drug absorption and permeability, solubility, and particle size. Together, these results indicate that this preliminary intestinal absorption model offers a simple and straightforward framework to build in complexities such as drug permeability, lipid partitioning, solubility, metabolism, and transport for improved prediction of the rate and extent of drug absorption.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Nagar S,Korzekwa RC,Korzekwa Kdoi
10.1021/acs.molpharmaceut.7b00286subject
Has Abstractpub_date
2017-09-05 00:00:00pages
3069-3086issue
9eissn
1543-8384issn
1543-8392journal_volume
14pub_type
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