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TCH-025 Long-Term Study of the Formation of Aggregates in Undiluted Bevacizumab 25 mg/ml
  1. J Hernández-Jiménez1,
  2. A Salmerón-García2,
  3. N Navas-Iglesias1,
  4. A Martínez-Ortega1,
  5. J Cabeza-Barrera3,
  6. LF Capitán-Vallvey1
  1. 1University of Granada, Analytical Chemistry, Granada, Spain
  2. 2Baza Hospital, Hospital Pharmacy Unit, Baza, Spain
  3. 3University Hospital San Cecilio, Hospital Pharmacy Unit, Granada, Spain

Abstract

Background Bevacizumab, the active substance of Avastin®, is a humanised monoclonal antibody that acts as angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is used to treat several cancers, including colorectal, lung, breast, kidney and ovarian. Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells.

Purpose To evaluate the stability of bevacizumab 25 mg/ml in solution for infusion, in terms of the formation of aggregates once the vial was open. The study was carried out for 15 days since the manufacturer only indicates chemical and physical in-use stability for up to 48 hours at 2°C to 30°C in sodium chloride 9 mg/ml (0.9%) solution for injection, if the solution was prepared in validated aseptic conditions. The manufacturer also indicates that the prepared solution should not be frozen.

Materials and Methods The study of the formation of the aggregates was carried out by using a size exclusion high performance liquid chromatography method with diode array detection method (SE-HPLC-DAD). Two different storage conditions, i.e. refrigerated at 4°C and frozen at −20°C were maintained for 15 days. Samples were characterised by chromatographic analysis immediately after the vial was opened. These chromatographic data were compared with those obtained on subsequent days. A stress study was also conducted.

Results Analysis of freshly-prepared samples enabled us to characterise bevacizumab chromatographically by SE-HPLC-DAD. In the corresponding chromatograms monomers were clearly detected (main peak in the chromatogram) at 7.7 ± 0.1 min of retention time, as was the presence of possible dimers at 6.0 ± 0.1 min (small chromatographic peak). Chromatographic analysis of the same samples stored at room temperature and protected from light in a refrigerator at 4°C indicated the absence of a peak at 6.1 ± 0.1, the shift of the main peak to 8.1 ± 0.1, and the detection of a new chromatographic peak at 9.5 ± 0.1.

Conclusions The results of this study indicated the absence of aggregate formation in bevacizumab 5 mg/ml during the period of monitoring (15 days) under the two storage conditions tested. Nevertheless, they clearly indicate some kind of break down.

Acknowledgement Financial support was provided by the Project PI10/00201 (Instituto Carlos III, Ministerio de Economía y Competitividad, Spain). We also want to thank the Hospital Pharmacy Unit of the University Hospital of San Cecilio which kindly supplied all the bevacizumab samples.

No conflict of interest.

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