2010 - Berlin - Germany

PAGE 2010: Applications- Oncology
Hoai-Thu Thai

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. Mentrť(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 Ķg/mL.

Conclusions: The present pharmacokinetic model for aflibercept characterizes well the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.

[1] Chu QS. Aflibercept: an alternative strategy for inhibiting tumour angiogenesis by vacular endothelial growth factors. Expert Opinion on Biological Therapy 2009 ; 9: 263-271.
[2] Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Loffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopouplos GD, Rudge JS. VEGF-Trap: A VEGF blocker with potent antitumor effects. PNAS 2002; 99(17): 11393-11398.
[3] Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn 2008; 35:573-591.
[4] Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 2001; 28(6): 507-530.

Reference: PAGE 19 (2010) Abstr 1828 [www.page-meeting.org/?abstract=1828]
Poster: Applications- Oncology
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