Acetate chaptecortave• 31 An

Diseases Retinal in Mechanisms and Drugs • 4 section

Acetate chaptecortave• 31 An

28.Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol 2006;142:660–668.

29.D’Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology 2003;110:2372–2383; discussion 2384–2385.

30.Russell SR, Hudson HL, Jerdan JA. Anecortave acetate for the treatment of exudative age-related macular degeneration – a review of clinical outcomes. Surv Ophthalmol 2007;52(Suppl. 1):S79–S90.

31.Slakter JS, Bochow TW, D’Amico DJ, et al. Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration. Ophthalmology 2006;113:3–13.

32.Klais CM, Eandi CM, Ober MD, et al. Anecortave acetate treatment for retinal angiomatous proliferation: a pilot study. Retina 2006;26:773–779.

33.Eandi CM, Ober MD, Freund KB, et al. Anecortave acetate for the treatment of idiopathic perifoveal telangiectasia: a pilot study. Retina 2006;26:780–785.

34.Bressler NM. Verteporfin therapy in age-related macular degeneration (VAM): an open-label multicenter photodynamic therapy study of 4,435 patients. Retina 2004;24:512–520.

35.Postelmans L, Pasteels B, Coquelet P, et al. Severe pigment epithelial alterations in the treatment area following photodynamic therapy for classic choroidal neovascularization in young females. Am J Ophthalmol 2004;138:803–808.

36.Schlotzer-Schrehardt U, Viestenz A, Naumann GO, et al. Dose-related structural effects of photodynamic therapy on choroidal and retinal structures of human eyes. Graefes Arch Clin Exp Ophthalmol 2002;240:748–757.

37.Wachtlin J, Behme T, Heimann H, et al. Concentric retinal pigment epithelium atrophy after a single photodynamic therapy. Graefes Arch Clin Exp Ophthalmol 2003;241:518–521.

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39.Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444.

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41.Regillo CD, D’Amico DJ, Mieler WF, et al. Clinical safety profile of posterior juxtascleral depot administration of anecortave acetate 15 mg suspension as primary therapy or adjunctive therapy with photodynamic therapy for treatment of wet age-related macular degeneration. Surv Ophthalmol 2007;52(Suppl. 1):S70–S78.

42.D’Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy. Retina 2003;23:14–23.

KEY FEATURES

Vascular endothelial growth factor-A (VEGF-A) has become a frequent target for the treatment of ocular diseases in which angiogenesis plays a role as a result of the growing body of evidence that it is an important regulator of angiogenesis, vascular development and differentiation, and vascular permeability. Several anti-VEGF therapies have become available for clinical use. This chapter will discuss the pharmacokinetics of bevacizumab, an anti-VEGF antibody.

INTRODUCTION AND HISTORY

The development of a vascular supply is essential for tissue repair and reproductive functions; thus, normal angiogenesis is vital for proper functioning of the human body. Angiogenesis is also implicated in the pathogenesis of a variety of systemic disorders, such as autoimmune diseases (e.g., rheumatoid arthritis, psoriasis), as well as in tumor growth and metastasis. It is also involved in the pathogenesis of ocular diseases, such as proliferative retinopathies, age-related macular degeneration (AMD), and others. Vascularization plays a unique role in the exchange of secretory products between the interstitial fluid surrounding the parenchymal cells and the plasma.1,2

A breakthrough in the understanding of normal and pathological angiogenesis occurred in 1948. Michaelson proposed that the existence of a diffusible angiogenic, “factor X,” produced by the retina is responsible for retinal and iritic neovascularization that occurs in proliferative diabetic retinopathy (PDR) and other retinal disorders, such as central retinal vein occlusion (CRVO).3

It took another 20 years until another breakthrough was achieved from a different direction. In 1968, the first experiments to test the hypothesis directly that tumors produce angiogenic factors were performed. Greenblatt and Shubik4 and Ehrmann and Knoth5 demonstrated that transplantation of melanoma cells or choriocarcinoma cells promoted blood vessel proliferation even when a millipore filter was interposed between the tumor and the host, providing evidence that tumor angiogenesis was mediated by diffusible factors produced by the tumor cells. In 1971, Folkman et al.6 proposed that antiangiogenesis may be an effective approach in treating human cancer. Folkman et al.6 initiated the first efforts aimed at isolating a “tumor angiogenesis factor” from human and animal tumors. In 1985, the purification to homogeneity and sequencing of both acidic (aFGF) and basic fibroblast growth factors (bFGF) were reported, and in the subsequent year their cDNAs were cloned. It also became clear that these molecules are not efficiently secreted and are mostly cell-associated.7

Independent and unrelated lines of research converged toward the identification of VEGF. In 1983, Senger et al.8 described the partial purification of a protein capable of inducing vascular leakage in the skin from the conditioned medium of a guinea pig tumor cell line and named the protein “tumor vascular permeability factor” (VPF). The authors proposed that VPF could be a mediator of the high permeability of tumor blood vessels. In a later publication, they reported the purification and NH2-terminal amino acid sequencing of guinea pig VPF.8 In

1989, Ferrara and Henzel reported the isolation of a diffusible endothelial cell-specific mitogen from medium conditioned by bovine pituitary follicular cells, which they named “vascular endothelial growth factor” to reflect the restricted target cell specificity of this molecule. NH2- terminal amino acid sequencing of purified VEGF proved that this protein was distinct from the known endothelial cell mitogens, such as aFGF or bFGF, and that they did not match any known protein in available databases.9 Connolly et al.10 continued the work by Senger et al. and independently reported the isolation and sequencing of human VPF from U937 cells. cDNA cloning of VEGF and VPF, also reported in 1989, demonstrated that VEGF and VPF were the same molecule. The finding that VEGF is potent, diffusible, and specific for vascular endothelial cells led to the hypothesis that this molecule might play a role in the regulation of physiological and pathological growth of blood vessels.11

It emerged that this hypothesis was correct, with VEGF having been proven able to promote growth of vascular endothelial cells derived from arteries, veins, and lymphatics. VEGF is also a survival factor for endothelial cells and prevents endothelial apoptosis. It plays a role in the enhancement of vascular permeability and hemodynamic effects. Although endothelial cells are the primary targets of VEGF, several studies have reported mitogenic effects also on certain nonendothelial cell types, such as retinal pigment epithelial cells, pancreatic duct cells, Schwann cells, alveolar type II cells and other cells. VEGF has the ability to promote monocyte chemotaxis and was reported to have hematopoietic effects, inducing colony formation.7

From the ocular point of view, angiogenesis is a basic and critical part in the pathogenesis of many ocular neovascular syndromes and their complications. VEGF-A is believed to play a significant role in the formation of blood vessels that grow abnormally and leak. These blood vessels are fragile and can bleed, and potentially cause distortion of the retina, leading to deterioration of central vision.

Several strategies to inhibit the action of VEGF have been explored, including neutralizing anti-VEGF antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, inhibitors of VEGF receptor function, and upstream inhibitors of VEGF regulators such as protein kinase C. Bevacizumab (Avastin) is a recombinant humanized monoclonal immunoglobulin antibody that inhibits the activity of VEGF (see section on drug mechanism, below). It was designed as antitumor treatment in order to treat advanced carcinoma patients. Ranibizumab (Lucentis) is also a humanized antibody fragment against VEGF which was specifically designed for intraocular use as a smaller antibody fragment to penetrate through the retina better. The Food and Drug Administration (FDA) approved ranibizumab for treatment of subfoveal neovascular AMD in June, 2006. It was the first treatment for AMD shown to improve visual acuity (VA) in a substantial percentage of patients as opposed to slowing visual loss. A number of prospective, double-blind, placebo-controlled studies have proven its efficacy in treating minimally classic or occult choroidal neovascularization (CNV) secondary to AMD12 as well as predominantly classic CNV.13 Bevacizumab has a similar action and is related to the ranibizumab compound with respect to its structure. Bevacizumab was first approved by the FDA for the treatment of metastatic colorectal cancer in 2004, but it has not gained approval for intravitreal use. It has, however, recently been reported to treat patients successfully with a number of ocular diseases with off-label use.