Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis

Abstract

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.

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

“…Necitumumab exhibits nonlinear PK, indicating target‐mediated disposition consistent with therapeutic mAbs 4, 5, 6, 7, 8, 9. Covariate analysis did not indicate any patient factors such as gender, age, race, disease status, renal function, hepatic status, or baseline tumor load, while weight had a small contribution, all in concordance with previous findings of IgG‐type mAbs in oncology 8, 10.…”

Mathematical analysis of the pharmacokinetic–pharmacodynamic (PKPD) behaviour of monoclonal antibodies: Predicting in vivo potency

“…which is very similar, but not quite the same, as the previous approximation y (1) min given in (13). Converting back to the original coordinates gives…”

“…Although originally proposed to describe the effects of extensive drug-target binding in tissues, TMDD has received most interest as a saturable clearance mechanism (due to, for example, receptor-mediated endocytosis; see [13]) for biologics, specifically mAbs. One specific example of the impact of mechanism-based PKPD models based on TMDD principles in drug discovery and development comes from the area of anti-IgE mAbs.…”

“…A systematic analysis of how mechanistic TMDD models can be employed in potency estimation of candidates is not yet available. Inspired by the beforementioned case studies and recent examples of how a rigorous mathematical analysis can aid our understanding of complex pharmacological systems and provide tools to predict essential PKPD properties of mAbs [16,10,13] we explore the behaviour of a TMDD model with respect to the relationship between the target affinity of the mAb and its in vivo potency. Section 1 gives the background for this study and section 2 describes the model development from the reaction mechanism.…”

Dynamics of target-mediated drug disposition

“…Recently, Yan et al [15] analysed the relationship between TMDD-and Michaelis-Menten type dynamics. We also mention the work by Krippendorff et al [16] which studies an extended TMDD system which includes receptor trafficking in the cell.…”