Target-mediated drug disposition and dynamics

Abstract

Nonlinear pharmacokinetics and pharmacodynamics may result from several capacity-limited processes and often represent complicating factors in characterizing the pharmacological properties of drugs. Target-mediated drug disposition (TMDD) corresponds to a special case wherein a significant proportion of a drug (relative to dose) is bound with high affinity to a pharmacological target, such that this interaction is reflected in the pharmacokinetic properties of the drug. Dose-dependent effects on apparent pharmacokinetic parameters may manifest, including the steady-state volume of distribution and total systemic clearance. Although a few small molecular weight compounds have been identified to exhibit TMDD, the incidence of TMDD is likely to increase particularly among emerging biotechnology pharmaceuticals. The goal of this commentary is to describe the basic tenets of TMDD and discuss several mathematical modeling approaches for characterizing this phenomenon. Whereas traditional pharmacokinetic/pharmacodynamic models assume that the amount of the drug–target complex is negligible relative to the total amount of drug in the body, integrated mechanism-based models of TMDD incorporate the binding and stoichiometry of drug–target binding. These models may be utilized to infer the time-course of inaccessible system variables, such as the in vivo density of the drug–target complex, and provide a suitable platform for ascertaining the apparent pharmacodynamic implications of TMDD.

Introduction

Nonlinear conditions in drug disposition and pharmacological effects are encountered frequently, and dose-dependent pharmacokinetic (PK) and pharmacodynamic (PD) processes complicate the characterization of drug concentration-effect and -toxicity relationships [1], often with significant clinical implications [2]. The fundamental principle that governs this behavior is that of capacity-limitation, where limited densities of enzymes or other proteins result in saturable processes and disproportionate changes in net drug exposure or responses with increasing dose. Levy introduced the term target-mediated drug disposition (TMDD) in reference to the observation that for some drugs, the capacity-limited substance responsible for their complex nonlinear pharmacokinetics was in fact the pharmacological target of the compound [3]. Whereas plasma concentrations of most drugs greatly exceed receptor or target concentrations, agents exhibiting TMDD are bound with high affinity and to a significant degree (relative to dose), such that this interaction influences the temporal profile of plasma drug concentrations. Although originally posed to describe the effects of extensive drug–target binding in tissues, TMDD has received considerable interest owing in part to its role in saturable clearance mechanisms for specific peptide and protein pharmaceuticals (e.g., receptor-mediated endocytosis) [4], [5]. The utilization of lower doses of these potent compounds, coupled with the means for detecting relatively low drug concentrations in biological fluids offered by advanced analytical methods, further increases the probability of observing this phenomenon.

The pharmacokinetic characteristics imparted by TMDD are now well recognized; however, systematic approaches for understanding the pharmacodynamic implications of TMDD are still in early development. For some compounds, there is an apparent disconnect between the time-course of target-occupancy and the pharmacological response [3]. Pertinent aspects of the in vivo pharmacological properties of drugs derive from the integration of PK/PD systems [6], and progress in comprehending the significance of TMDD will most likely be made through an iterative consideration of experimental data and mechanism-based modeling. This paradigm should yield opportunities for the rational design of new analogues and/or delivery systems for drugs with TMDD properties, as well as clinical dosing regimens that optimize pharmacotherapy across populations and for individual patients.