A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects

作者：Thai Hoai Thu^*; Veyrat Follet Christine; Vivier Nicole; Dubruc Catherine; Sanderink Gerard; Mentre France; Comets Emmanuelle

来源：British Journal of Clinical Pharmacology, 2011, 72(3): 402-414.

DOI：10.1111/j.1365-2125.2011.04015.x

• aflibercept
• MONOLIX
• population pharmacokinetics
• target-mediated drug disposition
• VEGF

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(-1) and 0.14 l day(-1), respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day(-1) and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 mu g ml(-1). Interindividual variability of model parameters was moderate, ranging from 13.6% (V(max)) 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.

• 出版日期2011-9