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

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 lympho-cytes 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 lympho-cyte 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.

A mathematical analysis of rebound in a target-mediated drug disposition model: I.Without feedback

“…Meno-Tetang and Lowe (2005)). However, in some cases, the complex is eliminated faster than the antibody due to factors such as interference of antigen binding on antibody salvage mechanisms (e.g.…”

“…This could, in turn, result in modified concentrations of the target protein in blood and in other organs. For example, binding and neutralisation of cytokines such as interleukins by blocking/neutralising antibodies causes an increase in the total levels of the cytokine (Meno-Tetang and Lowe, 2005). This increase is due to the blockade of the clearance pathways for the cytokine -the large drug-target complex cannot be cleared through the kidneys and since the complex cannot bind to the target, target-mediated clearance is also impaired.…”

The Application of Target Information and Preclinical Pharmacokinetic/Pharmacodynamic Modeling in Predicting Clinical Doses of a Dickkopf-1 Antibody for Osteoporosis

“…The anticipated LLOQ of the PF-04840082 bioanalytical assay is shown to represent the futility of dosing lower than predicted MABEL (top). taneously analyzed, this model has been used to provide a direct link between dose, exposure, and response (Meno-Tetang and Lowe, 2005;Ng et al, 2006;Wu et al, 2006). In this case, the TMDD model was used to simultaneously fit antibody, PF-04840082, and target, Dkk-1, concentrations in the rat and monkey after intravenous administration of PF-04840082 at several dose levels.…”

Effect of antigen binding affinity and effector function on the pharmacokinetics and pharmacodynamics of anti-IgE monoclonal antibodies

“…9 This increase in the magnitude of total IgE response for both HAE1 and HAE2 compared with omalizumab likely reflects the increased binding affinity for IgE. 18 The significantly greater increase in total IgE observed for HAE2 compared with HAE1 is likely again directly related to reduced interaction of IgE-HAE2 complexes with FcγR, thereby decreasing clearance of these complexes via this pathway.…”