• Treatment
• Visudyne ®
• Therapy at a glance
• CNV
• Therapy - a selective approach
• Clinical Development
• Efficacy
• Safety
• Pharmacokinetics
• Pharmacodynamics
• Administration
• Patient Information
• References

Pharmacodynamics

Ocular effects
Potential for selective vascular occlusion
Dose determination
Toxicology
Single-dose (acute) toxicity
Multiple-dose (chronic) toxicity
Skin photosensitivity
Hepatic effects
Reproductive toxicology
Placental transfer
Nursing mothers
Mutagenicity
Carcinogenicity
Cardiovascular effects

Several animal models have been used to investigate the effects of Visudyne^® therapy on healthy ocular structures and to investigate the vaso-occlusive potential of Visudyne^® therapy in CNV. Occlusion of the neovasculature was determined using ophthalmic fundus findings, fluorescein angiography, and histopathologic examination of the treated area. The clinical relevance of these effects is not known.

The potential of Visudyne^® therapy to achieve selective vascular occlusion was first demonstrated in the rabbit choroid.⁶⁴ The timing of light application after intravenous Visudyne^® administration was found to be critical for selective occlusion of the choriocapillaris without damage to the neural retina and Bruch’s membrane.

Visudyne^® therapy was subsequently shown to occlude experimental corneal neovascularization.⁵⁷ Neovascularization was induced in the rabbit cornea to provide an easily accessible monolayer-like neovascular net within a transparent matrix. Complete and irreversible neovascular occlusion was achieved with light doses of ?10 J/cm2 (light intensity 100 mW/cm2) applied 1 hour after injection of Visudyne^® 2 mg/kg. The extent of damage to vascular endothelial cells was found to be dependent on the dose of light. Histology revealed selective endothelial damage, with adjacent corneal stroma and iris vessels remaining intact.

Further evidence of endothelial membrane disintegration and thrombosis leading to prominent vascular occlusion was demonstrated in subretinal models of neovascularization. These had been developed by the implantation of highly vascularized non-pigmented or pigmented tumors in the rabbit choroid.60 In both models, the treatment response was maintained for at least 1 month of follow-up.

Extensive experiments with thermal laser-induced neovascularization in primate eyes (Ryan’s model) determined the optimal treatment parameters for effective and selective closure of CNV with Visudyne^® therapy.^107-110 The effects of various Visudyne^® doses and infusion rates, light doses and light intensities, and the timing of light application after Visudyne^® infusion were investigated and animals were monitored for up to 7 weeks after treatment (Table 8.1).^107-110

Table 8.1: Dosimetry of Visudyne^® therapy for experimentally induced CNV in monkeys

These studies confirmed that by controlling the Visudyne^® dose, light dose, and timing of light application, the effect of Visudyne^® therapy can be selective for the choroidal neovasculature, with minimal effects on the surrounding retina and choroid.^107-110 Closure of choroidal neovasculature was demonstrated angiographically and confirmed histologically, with damage to endothelial cells apparent several hours after treatment (Figure 8.1).¹⁰⁹ There was no associated damage to the neural retina, retinal vessels, and large choroidal vessels. Furthermore, there was minimal damage to photoreceptors and a dose-dependent recovery of the RPE and choriocapillaris after repeat treatments of Visudyne^® therapy in normal monkey eyes.^108,111

Maximal closure of choroidal neovasculature was achieved using Visudyne^® 0.375 mg/kg with light application 20–50 minutes after Visudyne^® injection at a light dose of 150 J/cm2 (light intensity 600 mW/cm2).¹⁰⁹ Lower doses of Visudyne^® were more selective for choroidal neovascular tissue, reduced damage to surrounding tissues, and permitted a shorter time interval between Visudyne^® infusion and light application.¹⁰⁹ The speed of Visudyne^® infusion had no effect on the rate of uptake of Visudyne^® into the choroidal neovasculature.¹⁰⁷ Light intensities of 300 or 600 mW/cm2 enabled shorter, more practical treatment times and were not accompanied by any apparent adverse effects.¹¹⁰ Light doses of 50–600 J/cm2 stopped fluorescein leakage from choroidal neovasculature, but doses of ?400 J/cm2 were associated with unacceptable toxicity in normal retinal tissues.¹⁰³ These parameters formed the basis for phase I/II dose-finding studies in patients with CNV.

Figure 8.1 Photomicrographs of CNV in the cynomolgus monkey 24 hours after treatment with Visudyne 0.375 mg/kg. Light
was applied 20 minutes after Visudyne injection at a dose of 150 J/cm2 (light intensity 600 mW/cm2).

Toxicology

Cell and tissue damage induced by Visudyne^® therapy is limited by the inherent selectivity of the therapy and the rapid clearance of the drug.⁵⁰ In addition to the selective accumulation of verteporfin in the neovasculature (animal models indicate that it is also present in the retina), the cytotoxic activity of verteporfin is restricted to the target tissue by directing light application to the area containing this tissue. Therefore, verteporfin remains inactivated in tissues where no light is applied. Additionally, adjacent structures are spared because singlet oxygen has a very short half-life (in the order of nano- to microseconds), so cellular damage is restricted to the immediate vicinity of singlet oxygen generation.⁵⁰ Nevertheless, the potential for toxicity in the eyes and skin remains while they continue to be exposed to normal outdoor light and strong, especially halogen, indoor light.

Extensive toxicology studies have been carried out to evaluate toxicity caused by verteporfin administered alone without light, or verteporfin followed by light application. In all studies the injected dose of verteporfin was at least twice the 6 mg/m2 BSA (approximately 0.15 mg/kg) dose used clinically.

Acute toxicity was studied in rats and dogs given a single intravenous dose of verteporfin 0.2–20 mg/kg with and without light application. Light, when given, was applied 3 hours after verteporfin administration, at wavelengths used clinically to activate verteporfin (687–713 nm), to an area of the skin of the hind limb.¹⁰³ Animals were monitored for up to 2 weeks and there was no evidence of systemic toxicity. Verteporfin produced local, deeptissue damage of the hind limb only when activated by light. The degree of damage was related to the dose of verteporfin and the light dose.

Multiple-dose studies in rats and dogs given intravenous verteporfin with and without light application showed treatment-related hematopoietic effects in the bone marrow, liver, and spleen only at doses at least 66 times higher than the single 6 mg/m2 BSA (approximately 0.15 mg/kg) dose of Visudyne^® used clinically at 3-month intervals.¹⁰³

Skin photosensitivity is an obvious potential complication of any photodynamic therapy. Skin photosensitivity caused by verteporfin has been investigated in mice, rabbits, and pigs.^104,112,113 There were differences between species in skin sensitivity to verteporfin and light, with pig skin reacting most like human skin. These studies showed that skin photosensitivity was highest when light was applied immediately after verteporfin injection.

Studies in rabbits and pigs showed that skin photosensitivity correlated well with plasma levels of verteporfin.¹⁰³ Skin photosensitivity was tested after intravenous verteporfin administration (0.5–2.0 mg/kg) and light doses of 5–275 J/cm2 applied 0.5–5 hours after verteporfin injection. Skin photosensitivity to low light doses (<100 J/cm2) lasted only 4–5 hours after injection of verteporfin 1 mg/kg.

Exposure of the skin to ambient indoor light will help inactivate residual verteporfin in the skin through a process called photobleaching.

No evidence of hepatotoxicity was found in rats and dogs administered verteporfin at doses 10–20 times higher than the maximum dose investigated clinically.¹⁰³

Developmental toxicity studies of intravenous verteporfin in rats and rabbits showed no adverse effects on embryo or fetus viability, weight, or morphology when administered at maternally toxic doses of 10 mg/kg/day.¹⁰³ Higher doses of 25 mg/kg/day for 10 days (218 times the exposure of the recommended human dose based on AUC) increased the incidence of common abnormalities in rat fetuses. A decrease in body weight gain and food consumption was observed in pregnant rabbits given verteporfin, ?10 mg/kg/day for 13 days. The no observed effect level (NOEL) for maternal toxicity was 3 mg/kg/day and for developmental toxicity, 10 mg/kg/day.

Verteporfin does not accumulate in the fetus.103 Radioactively labeled verteporfin 25 mg/kg was administered to pregnant rats on day 15 of gestation. Radioactivity was highest 5 minutes after injection and was 4-fold lower in the placenta and 135-fold lower in the fetus than in maternal plasma.

It is not known whether verteporfin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised by nursing mothers who have received Visudyne^® therapy.

Several in vitro and in vivo studies including microbial mutagenicity, unscheduled DNA synthesis, mammalian point mutation, chromosome aberration, and micronucleus assay have shown that verteporfin is not mutagenic or clastogenic in the absence or presence of light application.¹⁰³

The potential for DNA damage with verteporfin has not been studied. However, DNA damage that may result in chromosomal aberrations, sister chromatid exchanges, and mutations have been reported in animal studies of other photodynamic therapeutic agents. It is not known how the potential for DNA damage translates into human risk.

No studies have been conducted to evaluate the carcinogenic potential of verteporfin.

The cardiovascular effects of intravenous verteporfin at doses of up to 20 mg/kg have been studied in mice, rats, dogs, rabbits, pigs, and monkeys.¹⁰³ Serious adverse cardiovascular effects have been observed only in anesthetized or sedated pigs at a dose of 2 mg/kg infused at a rate of 0.75 mg/kg/min (50-fold greater than the rate of infusion used clinically), possibly as a result of complement activation. The cardiovascular effects were dependent on infusion rate, occurring with a fast infusion only, and were diminished or abolished by predosing with antihistamine. Furthermore, cardiovascular effects occurred only in anesthetized or sedated pigs; conscious pigs and other species (conscious or anesthetized) showed no adverse cardiovascular effects. Verteporfin at more than five times the expected plasma concentration in treated patients caused a low level of complement activation in human blood in vitro. There is no clinical experience of Visudyne^® therapy in anesthetized or sedated patients.

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