Application of a Convective-Dispersion Model to Predict In Vivo Hepatic Clearance from In Vitro Measurements Utilizing Cryopreserved Human Hepatocytes

Ryan      Niro; James   P.   Byers; Ronald   L.   Fournier; Kenneth      Bachmann

Abstract

Growing interest in the prediction of in vivo pharmacokinetic data from purely in vitro data has grown into a process known as the in vitro-in vivo correlation (IVIC). IVIC can be used to determine the viability of new chemical entities in the early drug development phases, leading to a reduction of resource spending by many large pharmaceutical companies. Here, a convective-dispersion model was developed to predict the total hepatic clearance of six drugs using pharmacokinetic data obtained from in vitro metabolism studies in which the drug disappearance from suspensions of human cryopreserved hepatocytes was measured. Predicted in vivo hepatic clearances estimated by the convective-dispersion model were ultimately compared to the actual clearance values and to in vivo hepatic clearances that were scaled based on the well-stirred model. Finally, sensitivity studies were performed to determine the dependence of hepatic clearance on a number of physiological model parameters. Results reaffirmed that low clearance drugs exhibit rate-limited metabolism, and their hepatic clearances are thus independent of blood flow characteristics, whereas drugs with relatively higher clearance values show a more pronounced dependence on the flood flow properties of dispersion and convection. Absent a priori knowledge about the flow-dependent properties of a drugs clearance, the convective dispersion model applied to disappearance data acquired from cryopreserved human hepatocytes is likely to provide satisfactory estimates of hepatic drug clearance.

Keywords: Hepatic, pharmacokinetic, hepatocytes

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