Target-Mediated Drug Disposition Model to Describe Non-linear Kinetics of a Monoclonal Antibody
E. Rouits, M. Lovern, M.L. Sargentini-Maier
UCB Pharma S.A.
Introduction: CDP791 is a Monoclonal antibody (Mab) showing non-linear pharmacokinetics. It is a VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2) antagonist developed for use in cancer therapy.
Objectives: To develop a target-mediated drug disposition (TMDD) model to:
i) explain the non-linear pharmacokinetic (PK) behavior observed with this Mab.
ii) identify and characterize the covariate effects on the PK behavior of CDP791.
Methods: Data were available from a phase II study in patients with Stage IIIb or Stage IV non-squamous non-small cell lung cancer requiring chemotherapy. A Target-Mediated Drug Disposition (TMDD) model was implemented in NONMEM. It included a central and a peripheral compartment as well as a third compartment (binding compartment) linked to the central, to model drug/target binding. A linear clearance was defined from the central compartment as well as distribution parameters with the peripheral compartment. Elimination from the binding compartment was nonlinear and dependent on the prevalence of both the drug and the receptor.
Biological and physiological parameters were tested as covariates on the BASE model based on their implication in the VEGF/VEGFR-2 loop and their potential impact on the drug/target binding.
Results: This TMDD model with two compartments (central and peripheral) and a third one for the drug/target binding described the PK adequately. The volume for the central compartment was around 3 L, which is closely similar to plasma volume. Linear clearance was 0.0101 L.h-1. Those values are consistent with pharmacokinetic parameters reported for other macromolecules presenting TMDD behavior[1]. The target/drug binding was faster than both degradation and synthesis of the target, as is generally expected for the kinetics of such processes.
The binding of drug to free target decreased in inverse proportion to plasma s-VEGFR-2 (up to a factor 10 between extreme values) or platelet count at baseline (up to a factor 2.5 between extreme values).
Linear clearance appeared to increase with increasing tumor size although in a moderate proportion (± 25%, compared to a typical subject)
Conclusions: We have developed a specific TMDD model that describes adequately the PK of CDP791.
Some biological parameters such as the s-VEGFR-2 and platelet count at baseline might be key parameters to consider if one wants to identify sub-populations of patients exhibiting differing CDP791 PK behaviors.
This TMDD model could be adapted to other Mabs that also present non-linear PK. Appropriate covariate analysis could also be adapted based on the characteristics of the Mab in question.
References:
[1] Lobo ED, Hansen RJ and Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 2004 Nov; 93(11): 2645-68.