A multiscale computational tool to simulate the PK of orally-administered drugs in the human GI tract

A multiscale computational tool to simulate the PK of orally administered drugs in the human GI tract Project Summary AbstractMost FDA approved drugs are administered orallydespite the complex process of oral drug absorption that is difficult to analyze experimentallyOral bioavailability is dependent on the interplay between multiple and simultaneous processes that are dependent on both the drug compound as well as the physiological and anatomical states of the userDue to this complexitycomputational models have emerged as a tool to integrate these factors in an attempt to mechanistically capture and predict the process of oral absorption in a robust and accurate mannerThe current predictive models are generallyD compartmental models and are thus limited by simplified physiological characteristics of the gastrointestinal tractGITby semi empirical or specific analytical solutions of dissolution profilesand by insufficient descriptions of interactions between delivery vehicles and the GITIn particularthe absorption can be incorrectly modelled using theD models forisome drug classesunder the BCS schemeiifor GITwhose sizes are significantly different from the median human andiiifor drugsthat are meant to target specific regionsfor instancethe drugs used to treat some colon cancerby incorrectly predicting the absorption in other regionsIn this projectwe propose to develop an efficient and spatially accurate computational tool to simulate the dissolutiontransportLiberationAbsorptionDistributionMetabolismEliminationand ToxicityLADME Tof orally administered drugs in the human GIT at the enzymedelivery vehicleintestine tissueand GIT levelsThis will be further combined with the compartmental model at the whole body level to predict systemic pharmacokineticsIn Phase Ithe multiscale computational tool will be constructed by integrating the spatially accurate first principles driven highfidelity drug transportdissolution and absorption model in the human stomach and GITmechanistic drug release modelsand the multi layer intestine physiologically based pharmacokineticslumenenterocyteand blood layersmodelsThese will be accomplished using the recently demonstrated CFD Research Corporation s spatially accurate Q D frameworkIn Phase IIwe willitest and validate the models for drug transport and absorption physics for theBCS classes of drugsiimorph the GIT to create variants corresponding to diseased specimens and different anatomical sizesiiiperform and validate the spatially accurate drug absorption simulations for these new GIT variantsivobtain the PK parameters and perform the drug absorption simulations for infants and childrenvlink the Q D GUT model to the whole body PK modelandviuse this multiscale modelto optimize specific casesincluding the drug delivery to target regionsThe multiscale software developed in this project will provide a powerful virtual platform in investigating LADME Tfacilitating in vitro in vivo scalingdesigning and developing targeted oral drug delivery systemsand evaluating safety and efficacy of oral drug productsUltimatelythe proposed tool will be developed into a commercial product to meet urgent demands from pharmaceutical and biomedical industries Project NarrativeThe novel software tool proposed in this project will provide an efficient and spatio temporally accurate multiscale computational platform to virtually testdesignand develop oral drug productsThis will be achieved by investigating interactions between drug delivery systems and the human physiological systems from enzyme levels to whole body levelsand by revealing key aspects affecting oral drug absorption and consequent therapeutic or toxic effectsThe developed tool will meet urgent demands from pharmaceutical and biomedical industries by accelerating drug discovery and development processesby facilitating translational applications from bench to bedsideby increasing success rates of new drug productsand by ultimately helping reduce the health care burdens on society