KEY FEATURES

●Verteporfin derives from porphyrin and is also known as the benzoporphyrin monoacid derivative.

●Verteporfin is a light-activated drug used in photodynamic therapy.

●Verteporfin has a peak absorption at a long wavelength that enables the activating nonthermal laser light to penetrate deep into the target tissue.

●Verteporfin selectively damages neovascular endothelial cells.

●The primary mechanism of photodynamic therapy with verteporfin is the immediate occlusion of neovessels within the target.

INTRODUCTION AND HISTORY

Verteporfin is a potent second-generation light-activated drug that selectively damages neovascular endothelial cells, occluding target vessels. It is derived from porphyrin and also known as the benzoporphyrin monoacid derivative. It is a chlorine-type molecule and is a 1 : 1 mixture of two regioisomers (Figure 43.1). Each of these regioisomers consists of an enantiomeric pair that demonstrates similar pharmacologic activity in vitro and in vivo.1 Verteporfin is used in photodynamic therapy (PDT).

PDT is a two-step process that includes the intravenous administration of a pharmacological photosensitizer combined with the physical activation of the substance by a nonthermal diode laser light in the red wavelength. Activation of the drug in the presence of oxygen results in the creation of singlet oxygen and free radicals that are toxic to cells and tissues within the immediate vicinity of the target area.2

PDT was first evaluated as a potential diagnostic and therapeutic tool about 25 years ago. It was used for the detection and treatment of skin metastasis in lung cancer and subsequently to evaluate the phototoxic effects in experimental cerebral tumours.3 Hematoporphyrin derivatives were used as dyes which were laser-activated to achieve the desired clinical effects.

Before the development of PDT with verteporfin, laser photocoagulation was the only treatment proven to be effective for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). However, retinal function was directly damaged by thermal energy, with a high risk of immediate and irreversible vision loss at the site of laser light application. In contrast to laser coagulation, no thermal tissue damage occurs after PDT, and retinal function is maintained.

Verteporfin became available on April 12, 2000, as the first Food and Drug Administration (FDA)-approved drug for patients with subfoveal neovascular AMD, and since 2001, for CNV in pathologic myopia. Thereafter, laser photocoagulation was not considered appropriate for the majority of subfoveal lesions or for poorly demarcated lesions, and its use was limited to a subset of patients with juxtafoveal or extrafoveal lesions in whom it confines vision loss to a smaller area than without treatment.

Verteporfin is a chlorine-type molecule and exists as an equal mixture of two regioisomers (Figure 43.1), each of which consists of an enantiomeric pair that demonstrate similar pharmacologic activity in vitro and in vivo.1 Verteporfin has a molecular formula of C41H42N4O8 and a relative molecular weight of 718.81. It is formulated in a lipid-based preparation that augments solubility in the blood.

Verteporfin has a long absorption wavelength with several peaks (Figure 43.2).1 The strongest absorption peak of verteporfin is at approximately 400 nm (blue light), but this wavelength is not clinically useful for treatment of CNV because it is the same as the absorption peak of oxyhemoglobin.2 Verteporfin absorbs light efficiently at a wavelength of 689 nm (red light), which can penetrate a thin layer of blood, melanin, or fibrotic tissue.1 Light at this wavelength is not absorbed strongly by naturally present substances, avoiding thermal damage to retinal tissues2 (Figure 43.2).

The most suitable light source for use in PDT with verteporfin is a nonthermal diode laser, operating at a wavelength of 689 ± 3 nm.1 The laser beam is delivered through a slit lamp to the affected area in the retina and the light is targeted to the desired area by means of a lowintensity helium-neon beam through a standard ophthalmologic contact lens. Two laser systems have been specifically designed and approved for use with PDT with verteporfin: the Coherent Opal Photoactivator laser and LaserLink adapter, and the Zeiss Visulas 690s laser and Visulink PDT adapter.

Following intravenous infusion, verteporfin exhibits a biexponential elimination with a terminal elimination half-life of approximately 5–6 hours and is eliminated from the body within approximately 24 hours.4 The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2.

Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine. At the intended dose of 6 mg/m2 body surface area, the pharmacokinetic characteristics of verteporfin are not significantly affected by age, gender, race, or mild hepatic or renal impairment, so dose adjustments are not required.4

DRUG MECHANISM

The four main stages of the mechanism of action of PDT with verteporfin are described in Figure 43.3.

In vitro studies suggest that lipophilic verteporfin is taken up by a process of receptor-mediated endocytosis via low-density lipoprotein (LDL) receptors.5 In the blood stream, circulating verteporfin forms complexes with LDL. It selectively accumulates within neovasculature, including neovascular endothelial tissue, probably due to increased uptake of LDL and increased expression of LDL receptors on rapidly proliferating cells.

Verteporfin Therapy: Photodynamic• 43 chapterand Photosensitizers

Figure 43.1  Chemical structures of verteporfin’s regioisomers I and II.

Wavelength (nm)

Figure 43.2  Excitation spectrum of verteporfin.

Once verteporfin has bound to surface receptors on endothelial cell membranes, it is taken up into the cell and binds to intracellular or cytoplasmic components.5

Application of the nonthermal laser to the target tissue causes verteporfin to transform from a ground singlet state to an excited triplet state.2

From its triplet state, verteporfin initiates photochemical reactions either directly via the formation of reactive free radicals (type I mechanism) or indirectly via the transfer of its energy into ground state oxygen (3O2) and highly reactive singlet oxygen (1O2) (type II mechanism).2 Both photochemical reactions can occur simultaneously and both cause direct and immediate cytotoxicity (Figure 43.3).

Reactive oxygen species can cause lipid and amino acid peroxidation, affecting cell membrane-associated and intracellular targets, and may produce a number of effects on immune cells.2 The effect is dependent on the doses of both photosensitizer and activating light. Induction of high levels of oxidative stress results in necrotic cell death, while lowerintensity oxidative stress initiates apoptosis. Sublethal doses of PDT may result in the modification of cell surface receptor expression and consequently influence cell activities.

The primary mechanism of action of PDT with verteporfin may be the damage to the fibrovascular tissue through the induction of immediate occlusion of vessels. Red and white blood cells, aggregated platelets, and fibrin can block the lumen of the neovasculature.2

Histologically, the endothelial cells lining the vessels are damaged; they are swollen and the nuclear membranes break. Other nearby vessels remain intact, while minimal damage may occur to adjacent retinal structures such as the overlying photoreceptors and retinal pigment epithelium (RPE).2

The effects on CNV in humans following PDT with verteporfin have been confirmed by the absence of leakage from CNV on fluorescein angiography after treatment. PDT with verteporfin may subsequently cause selective occlusion of vessels while sparing overlying retinal cells and Bruch’s membrane, thereby maintaining function of the retina and helping to reduce the risk of vision loss.2

DRUG EFFECTS IN HUMAN

NONOCULAR DISEASES

PDT IN ONCOLOGICAL DISORDERS

Mechanisms that have been shown to be involved in the tumoricidal effect of PDT with verteporfin include direct cytotoxicity to tumor cells and selective occlusion of the tumor vasculature, thus starving the tumor of oxygen or nutrients.

Thus, PDT has mostly been considered as a local therapy in which cell and tissue destruction happens primarily in the area that is exposed to light and the immediately surrounding areas. However, mounting evidence suggests that, as opposed to many common cancer therapies that are largely immunosuppressive, PDT can stimulate the immune system. In this respect PDT is similar to adjuvant-enhanced laser immunotherapy that has also been shown to be capable of destroying local tumors, while at the same time sensitizing the immune system to destroy distant metastases.6

Furthermore, PDT induces among numerous cell targets membrane damage and alteration in cancer cell adhesiveness, an important parameter in cancer metastasis.7

In order to increase its antitumor effects, PDT with verteporfin has been used in combination with other drugs. For example, it has been shown that paclitaxel augments the cytotoxic effect of PDT with verteporfin in gastric and bile duct cancer cells.

PDT has been used alone or in combination with surgery in many oncologic conditions, including gastrointestinal cancers, brain tumors, prostate cancer, skin melanoma, and primary, recurrent, and metastatic