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1.  A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects 
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 µg ml−1. Interindividual variability of model parameters was moderate, ranging from 13.6% (Vmax) 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.
doi:10.1111/j.1365-2125.2011.04015.x
PMCID: PMC3175510  PMID: 21575034
aflibercept; MONOLIX; population pharmacokinetics; target-mediated drug disposition; VEGF
2.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
doi:10.1208/s12248-010-9201-5
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence

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