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Research Letters |

Reduction of Vascular Endothelial Growth Factor A in Human Breast Milk After Intravitreal Injection of Bevacizumab but Not Ranibizumab FREE

Christoph Ehlken, MD; Gottfried Martin, MD; Andreas Stahl, MD; Hansjürgen Thomas Agostini, MD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology, University Eye Hospital Freiburg, Freiburg, Germany.


Arch Ophthalmol. 2012;130(9):1226-1227. doi:10.1001/archophthalmol.2012.112.
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Published online

Anti–vascular endothelial growth factor (VEGF) drugs such as bevacizumab (Avastin) and ranibizumab (Lucentis) are increasingly used in patients with choroidal neovascularization owing to causes other than wet age-related macular degeneration, such as myopia and chorioretinitis, and in patients with macular edema due to retinal vein occlusion or diabetes mellitus.1 These conditions often affect younger patients and include women of child-bearing potential. There are only very limited data about the use of anti-VEGF agents in pregnant or nursing women.

In this case study, serum and breast milk of a 32-year-old patient were analyzed for the concentrations of VEGFA and bevacizumab before and after intravitreal injection of bevacizumab and ranibizumab.

A 32-year-old woman, who was breastfeeding her 12-week-old son, was diagnosed as having scar-associated choroidal neovascularization in her left eye. Treatment with intravitreal bevacizumab was recommended. With preliminary data of VEGFA concentrations after the first injection of bevacizumab available, the treatment was changed to ranibizumab. After 3 injections, no signs of active choroidal neovascularization were detected. Informed consent was obtained before any study-related procedure was performed. The institutional review board waived approval. The study was conducted following the principles outlined in the Declaration of Helsinki.

The samples were analyzed by enzyme-linked immunosorbent assay using a commercially available kit for detection of VEGFA (R&D Systems, Inc) and for bevacizumab using a protocol similar to one described by Ziemssen et al.2

The VEGFA and bevacizumab levels in serum and breast milk are shown in Figure 1 and Figure 2, respectively. After 1 injection, the serum VEGFA level decreased rapidly within 1 week to a nondetectable level. During this time, bevacizumab was detected in the serum with a peak concentration after 1 week. After 3 weeks, a steady increase of the VEGFA serum level was measured until week 8. At this point, the clinical criteria for reinjection were met and ranibizumab was injected. Four days after ranibizumab injection, the VEGFA level decreased only by 10% and began to increase again after only 3 more days.

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Figure 1. Concentrations of vascular endothelial growth factor A (VEGFA) and bevacizumab in the serum.

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Graphic Jump Location

Figure 2. Concentrations of vascular endothelial growth factor A (VEGFA) and bevacizumab in breast milk.

After intravitreal treatment with bevacizumab, the VEGFA level in breast milk slowly decreased, from 13.3 ng/mL to 8.6 ng/mL after 2 weeks, marking a decrease of 35%. In the following weeks, the VEGFA level recovered slowly. Following the intravitreal injection of ranibizumab, the level of VEGFA in breast milk remained stable without significant alterations except for 1 outlier. No free bevacizumab was detected in breast milk at any time.

To our knowledge, this is the first description of a significant effect of treatment with intravitreal bevacizumab, but not ranibizumab, on VEGFA levels in serum and breast milk.

This distinction could be explained by a difference in the molecular structure of the proteins: whereas bevacizumab consists of a humanized IgG antibody with a fragment crystallizable (Fc) region, ranibizumab consists of only the fragment antigen-binding (Fab) region. It has been shown that Fc-containing antibodies can be transferred across the blood-retina barrier and the placenta via the Fc receptor of the neonate (FcRn).3,4 Both VEGFA and its receptors are important in the rodent mammary gland during pregnancy and lactation,5 and VEGFA receptors are expressed in the human newborn intestine, although their function has not yet been explained.6

Based on our data, the possibility of adverse events in the mother or the infant by reduction of the VEGFA levels in the serum or breast milk after intravitreal bevacizumab cannot be excluded. Consequently, in our opinion, if anti-VEGF treatment is required in nursing women, ranibizumab should be preferred to bevacizumab because of a lower effect on VEGFA levels in the serum and breast milk.

Correspondence: Dr Ehlken, Department of Ophthalmology, University Eye Hospital Freiburg, Killianstrasse 5, 79106 Freiburg, Germany (christoph.ehlken@uniklinik-freiburg.de).

Financial Disclosure: None reported.

Chang LK, Spaide RF, Brue C, Freund KB, Klancnik JM Jr, Slakter JS. Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration.  Arch Ophthalmol. 2008;126(7):941-945
PubMed   |  Link to Article
Ziemssen F, Zhu Q, Peters S,  et al; Tuebingen Bevacizumab Study Group.  Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: preliminary findings of a pilot study.  Int Ophthalmol. 2009;29(4):213-224
PubMed
Kim H, Robinson SB, Csaky KG. FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye.  Mol Vis. 2009;15:2803-2812
PubMed
Chaparro M, Gisbert JP. Transplacental transfer of immunosuppressants and biologics used for the treatment of inflammatory bowel disease.  Curr Pharm Biotechnol. 2011;12(5):765-773
PubMed
Pepper MS, Baetens D, Mandriota SJ,  et al.  Regulation of VEGF and VEGF receptor expression in the rodent mammary gland during pregnancy, lactation, and involution.  Dev Dyn. 2000;218(3):507-524
PubMed
Vuorela P, Andersson S, Carpén O, Ylikorkala O, Halmesmäki E. Unbound vascular endothelial growth factor and its receptors in breast, human milk, and newborn intestine.  Am J Clin Nutr. 2000;72(5):1196-1201
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Concentrations of vascular endothelial growth factor A (VEGFA) and bevacizumab in the serum.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Concentrations of vascular endothelial growth factor A (VEGFA) and bevacizumab in breast milk.

Tables

References

Chang LK, Spaide RF, Brue C, Freund KB, Klancnik JM Jr, Slakter JS. Bevacizumab treatment for subfoveal choroidal neovascularization from causes other than age-related macular degeneration.  Arch Ophthalmol. 2008;126(7):941-945
PubMed   |  Link to Article
Ziemssen F, Zhu Q, Peters S,  et al; Tuebingen Bevacizumab Study Group.  Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: preliminary findings of a pilot study.  Int Ophthalmol. 2009;29(4):213-224
PubMed
Kim H, Robinson SB, Csaky KG. FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye.  Mol Vis. 2009;15:2803-2812
PubMed
Chaparro M, Gisbert JP. Transplacental transfer of immunosuppressants and biologics used for the treatment of inflammatory bowel disease.  Curr Pharm Biotechnol. 2011;12(5):765-773
PubMed
Pepper MS, Baetens D, Mandriota SJ,  et al.  Regulation of VEGF and VEGF receptor expression in the rodent mammary gland during pregnancy, lactation, and involution.  Dev Dyn. 2000;218(3):507-524
PubMed
Vuorela P, Andersson S, Carpén O, Ylikorkala O, Halmesmäki E. Unbound vascular endothelial growth factor and its receptors in breast, human milk, and newborn intestine.  Am J Clin Nutr. 2000;72(5):1196-1201
PubMed

Correspondence

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