Abstract

It is well recognized that mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is a useful tool for the prediction of pharmacodynamic responses in humans. The role of PK/PD modelling in preclinical and clinical drug development is well established. In recent years, it has also been used in clinical settings to select the optimal dose and dosing regimen, thus supporting rational pharmacotherapy. PK/PD models link the drug concentration-time profile to the intensity of observed pharmacological response in order
to characterize the time-course of drug effect. They include drug disposition kinetics, biophase distribution, the biosensor process that involves the interaction between the drug and the pharmacological target, and sometimes also transduction processes. When a rapid equilibrium is obtained between plasma and biophase drug concentrations, simple models, such as the E[sub]max[/sub] or sigmoid E[sub]max[/sub] models may be utilized. For many drugs, however, pharmacological effect is delayed in relation to plasma concentrations and mechanistic models, for example indirect response models may be employed to account for this delay. The utilization of PK/PD models relies on suitable pharmacokinetic and pharmacodynamic measures that must be validated analytically and clinically in accordance with good laboratory and clinical practices. Immunosuppressant drugs exert different mechanisms of action. Thus, for the purpose of PK/PD modelling diverse markers of pharmacological response are proposed to describe the time course of drug effects including T-helper and T-cytotoxic lymphocyte trafficking responses (corticosteroids and FTY720), inhibition of enzyme activity (cyclosporine, tacrolimus and mycophenolic acid) or markers of mTOR signaling (everolimus), expression of T-lymphocyte activation antigens (antibodies), or in vitro and ex vivo lymphocyte responsiveness to mitogenic stimulation. In order to achieve adequate immunosuppression, these agents are very often administered in combination therapy. This may lead to clinically significant drug interactions. Among different approaches to study the nature of pharmacodynamic interactions between two or more immunosuppressive agents, besides classic isobolograms, model-fitting methods are very frequently used. The aim of this presentation is to provide an overview of recent advances in PK/PD modelling of immunosuppressive drugs and to indicate how modelling approaches may contribute to the improvement in immunosuppressive therapy.

Keywords: flu spray, malignant ascitis, plasma concentrations