Target-Mediated Drug Disposition
Numerous protein therapeutics are characterized by target-mediated drug disposition, which occurs when binding to the pharmacodynamic target structure affects the pharmacokinetics of a drug compound and results in capacity-limited, saturable processes (Levy, 1994). The consequence of these saturable processes caused by the limited availability of enzymes, receptors or other protein structures the drug is interacting with, is nonlinear pharmacokinetic behavior, i.e., plasma concentrations change dispro-portionately with increasing doses (Mager, 2006).
For conventional small molecule drugs, receptor binding is usually negligible compared to the total amount of drug in the body and rarely affects their pharmacokinetic profile. In contrast, a substantial fraction of a protein therapeutic can be bound to their pharmacologic target structure, for example a recep-tor. Target-mediated drug disposition can affect distribution as well as elimination processes. Most notably, receptor-mediated protein metabolism is a frequently encountered elimination pathway for many protein therapeutics that is often saturated at therapeutically used dosage regimens (see previous section) (Meibohm, 2004).
Nonlinearity in pharmacokinetics based on target-mediated drug disposition has for example been observed for several monoclonal antibody therapeutics, for instance for the anti-HER2 humanized monoclonal antibody trastuzumab. Trastuzumab is approved for the combination treatment of HER2 protein overexpressing metastatic breast cancer. With increasing dose level, the mean half-life of trastuzu-mab increases and the clearance decreases, leading toover-proportional increases in systemic exposure with increasing dose (Tokuda et al., 1999). Since trastuzu-mab is rapidly internalized via receptor-mediated endocytosis after binding to HER2, its target structure on the cell surface, saturation of this elimination pathway is the likely cause for the observed dose-dependent pharmacokinetics (Kobayashi et al., 2002).