Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis

Receptor mediated endocytosis (RME) plays a major role in the disposition of therapeutic protein drugs in the body. It is suspected to be a major source of nonlinear pharmacokinetic behavior observed in clinical pharmacokinetic data. So far, mostly empirical or semi-mechanistic approaches have been used to represent RME. A thorough understanding of the impact of the properties of the drug and of the receptor system on the resulting nonlinear disposition is still missing, as is how to best represent RME in pharmacokinetic models. In this article, we present a detailed mechanistic model of RME that explicitly takes into account receptor binding and trafficking inside the cell and that is used to derive reduced models of RME which retain a mechanistic interpretation. We find that RME can be described by an extended Michaelis–Menten model that accounts for both the distribution and the elimination aspect of RME. If the amount of drug in the receptor system is negligible a standard Michaelis–Menten model is capable of describing the elimination by RME. Notably, a receptor system can efficiently eliminate drug from the extracellular space even if the total number of receptors is small. We find that drug elimination by RME can result in substantial nonlinear pharmacokinetics. The extent of nonlinearity is higher for drug/receptor systems with higher receptor availability at the membrane, or faster internalization and degradation of extracellular drug. Our approach is exemplified for the epidermal growth factor receptor system

Dynamical evolution of the Au-197+Au-197 system at 15 MeV/nucleon

Collisions of a very heavy Au-197 + Au-197 system have been studied at an energy of 15 MeV/nucleon with the aim to investigate a possible change of the energy dissipation mechanism from one-body dissipation (presumably dominating at low excitation energies) to two-body dissipation. The experiment was carried out in 4 pi geometry using the CHIMERA multidetector array. A class of ternary events satisfying nearly complete balance of mass numbers was selected. Preliminary results suggest that the selected ternary events represent mostly prompt ternary partitions of the colliding system, in which the lightest fragment is quite massive. In the light of theoretical predictions of Carjan, Sierk and Nix this result may imply that the observed ternary reactions are driven by the two-body dissipation mechanism already at 15 MeV/nucleo

First results on isotopic studies in multifragmentation obtained with the CHIMERA 4 multide-tector

ibide

Study of the dissipative binary channels in the 107Ag + 58Ni reactions at 52 MeV/nucleon

XL Bormi