A mechanism-based model for the population pharmacokinetics of aflibercept in healthy subjects
H.T. Thai(1), C. Veyrat-Follet(2), N. Vivier (2), C. Dubruc(2), E. Comets(1), F. Mentré(1) , G. Sanderink(2)
(1)INSERM UMR738, University Denis Diderot Paris 7, Paris, France; (2)Global Metabolism and Pharmacokinetics Department, Sanofi-aventis, Paris, France
Objectives: Aflibercept (VEGF-Trap), a novel antiangiogenic agent that binds to VEGF, has been investigated for the treatment of cancer [1,2]. The aim of this study was to develop a mechanism-based pharmacokinetic model for aflibercept to characterize its binding to VEGF and its pharmacokinetic properties in healthy subjects.
Methods: Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentrations-time data were analyzed using a nonlinear mixed-effects modeling approach with MONOLIX 3.1.
Results: The best structural model involve two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment [3,4]. The typical estimated clearances for free and bound aflibercept were 0.88 L/day and 0.14 L/day, respectively. The central volume of distribution of free aflibercept was 5.05 L. The maximum binding capacity was 1.02 mg/day and the concentration of aflibercept corresponding to half of maximum binding capacity was 3.06 µg/mL.
Conclusions: The present pharmacokinetic model for aflibercept characterizes well the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.
References:
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[4] Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 2001; 28(6): 507-530.
