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A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects.
- Source :
- British Journal of Clinical Pharmacology; Sep2011, Vol. 72 Issue 3, p402-414, 13p, 1 Diagram, 1 Chart, 4 Graphs
- Publication Year :
- 2011
-
Abstract
- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Anti-angiogenic drugs have been developed as an effective therapeutic strategy for inhibiting tumour growth. However, their pharmacokinetics (PK) and their ligand inhibition properties have not been well characterized. The binding to a circulating target, such as vascular endothelial growth factor (VEGF), makes the PK of these drugs more complex. WHAT THIS STUDY ADDS • The underlying mechanism of disposition of aflibercept, where a saturable and high affinity binding of aflibercept to VEGF was adequately characterized by the Michaelis-Menten approximation of a target-mediated drug distribution model. To our knowledge, this is the first published mechanism-based population PK model for an anti-VEGF drug. AIM Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK 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 concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1. RESULTS The best structural model involved 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. The typical estimated clearances for free and bound aflibercept were 0.88 l day<superscript>−1</superscript> and 0.14 l day<superscript>−1</superscript>, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day<superscript>−1</superscript> and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml<superscript>−1</superscript>. Interindividual variability of model parameters was moderate, ranging from 13.6% ( V<subscript>max</subscript>) to 49.8% ( Q). CONCLUSION The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03065251
- Volume :
- 72
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- British Journal of Clinical Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 64114886
- Full Text :
- https://doi.org/10.1111/j.1365-2125.2011.04015.x