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Development of a PBPK model for drug-drug interaction of orally delivered drugs using in-vitro data

Freidig A, Onderwater R, Bogaards J, Bouzom F and Jochemsen R.

TNO Food and Nutrition Research, Zeist, The Netherlands; Servier, Paris, France

Early screening systems, like in-vitro preparations of human microsomes can give an indication whether or not a pharmacokinetic interaction between two drugs is possible. These systems are suited to indicate the presence of an interaction, but they score low in predicting the relevance of such an interaction for the clinical situation. The same holds true for screening systems of interactions on intestinal transport. Major factors that should be considered when interpreting in-vitro interaction data are: 1) the pharmacokinetics (Tmax and Cmax) of the inhibitor at the site of inhibition, 2) extrahepatic sites of interaction and 3) definition of the available concentration of substrate and inhibitor in both the in-vitro system and in-vivo, at the site of inhibition. To investigate the relevance of these factors a preliminary physiologically based pharmacokinetic model for oral dosing of CYP3A4 substrates and inhibitors has been constructed. The model includes a detailed description of the GI-tract and the liver and simulates the pharmacokinetics of two compounds. Compound specific parameters are taken from in-vitro measurements, where possible. The model was tested by using in-vitro interaction data of Midazolam and Ketoconazole to forecast the clinical effect of Ketoconazole on Midazolam pharmacokinetics.