On the Prediction of the Human Response: A Recycled Mechanistic Pharmacokinetic/Pharmacodynamic Approach

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Abstract
Although it is routine to predict the blood or plasma pharmacokinetics of compounds for man based upon preclinical studies, the real value of such predictions only comes when linked to drug effects. In the first example, the immunomodulator, FTY720, the first sphingosine-1-phosphate receptor agonist, stimulates the sequestration of lymphocytes into lymph nodes thus removing cells from blood circulation. A prior physiology-based pharmacokinetic model fitted the concentration-time course of FTY720 in rats. This was connected to an indirect response model of the lymphocyte system to characterise the cell trafficking effects. The IC(50) of FTY720 was different in the rat compared with the monkey; man was assumed to be similar to the monkey. The systemic lymphocyte half-lives were also different between species. To make predictions of the pharmacodynamic behaviour for man, two elements are required, i) systemic exposure, in this case from an upscaled physiology based model, and ii) an estimate of lymphocyte turnover in man, gained from the literature from other drug treatments. Predictions compared well with clinical results. The second example is the monoclonal antibody Xolair, designed to bind immunoglobulin E for atopic diseases. A mechanism based two-site binding model described the kinetics of both Xolair and endogenous IgE. This model has been reused for other monoclonal antibodies designed to bind fluid-phase ligands. Sensitivity analysis shows that if differences across species in the kinetics of the endogenous system are not accounted for, then pharmacokinetic/pharmacodynamic models may give misleading predictions of the time course and extent of the response.