What Is Verteporfin?

Vertepofen, its chemical names are 9-methyl (I) and 13-methyl (II) trans- (±) -18-ethylene-4,4a-dihydro-3,4-bis (methyl ester) ) -4a, 8,14,19-tetramethyl-23H, 25H-phenylporphyrin-9,13-dipropyl ester. This product is a dark green loose block. Verteporfin therapy is suitable for patients with secondary to age-related macular degeneration, pathological myopia, or suspicious ocular cytoplasmosis, which are typically dominated by concave central choroid neovascularization. There is no sufficient evidence to support verteporfin therapy in patients with occult subchoroidal neovascularization.

Chinese name: Vertepofen
Foreign name: Verteporfin

Molecular formula: C82H84N8O16
Molecular weight: 718.79
CAS: 129497-78-5

Introduction to Verteporfin Compounds

Vetiporfin Basic Information

Chinese name: Vetiporfin

Chinese alias: microtepofen

English name: Verteporfin

English alias: Verteporphin; trans-3,4-Dicarboxy-4,4a-dihydro-4a, 8,14,19-tetramethyl-18-vinyl-23H, 25H-benzo (b) porphine-9,13-dipropionic acid 3 , 4,9-trimethyl ester; Visudyne; VERTEPORFIN (200 MG);

CAS number: 129497-78-5

Molecular formula: C ₈₂ H ₈₄ N ₈ O ₁₆

Structural formula:

Molecular weight: 1437.59000

Exact mass: 1436.60000

PSA: 337.48000

LogP: 10.24600

Physiochemical properties of Vertepofen

Appearance and properties: dark green to black solid ^[1]

Verteporfin use

It is suitable for patients secondary to age-related ocular neovascularization, as well as pathological myopia or cytoplasmosis of the eye tissue.

Vetiporfin Overview

Verteporfin is a second-generation porphyrin photosensitizer that can be activated by light (wavelength 689nm) and can be used in photodynamic therapy to treat macular degeneration. The drug can selectively enter abnormal blood vessels, and irradiate with non-thermal laser light to generate active oxygen to occlude the abnormal blood vessels, thereby stopping the leakage of blood vessels and preserving vision.

After verteporfin is activated by light, cytotoxic products are formed in an aerobic environment. In this process, porphyrin transfers the absorbed energy to oxygen, forming a monooxygen with high activity and short duration. Monooxygen destroys various biological structures within its diffusion range. This process results in local vascular occlusion, cell destruction, and cell death under specific circumstances. In plasma, verteporfin is mainly carried by low-density lipoprotein (LDL). Photodynamic therapy (PDT) with verteporfin is selective. On the one hand, the choice of light irradiation site, on the other hand, the enhanced expression of LDL receptors in fast-proliferating cells, including choroidal neovascular endothelial cells, so that the fast-proliferating cells can selectively and quickly take up and accumulate vertepor Fen. Choroidal neovascularization has a faster and more selective uptake of verteporfin than retinal pigment epithelium, while other ocular structures contain very little drug. Therefore, choroidal neovascularization can be selectively destroyed. It is used in diseases such as wet age-related macular degeneration, pathological myopia, cytoplasmic cytoplasmosis, and other diseases that cause continuous deterioration or loss of vision, such as macular depression and choroidal neovascularization. ^[2]

Verteporfin pharmacological action

This product is a photosensitizer for photodynamic therapy. After administration, this product is mainly transported into the plasma by lipoproteins. In the presence of oxygen, this product is activated by light to generate highly reactive, singlet oxygen and reactive oxygen radicals that exist briefly. This product is a special light-sensitive injection for the treatment of age-related speckle degeneration in patients with clearly typical inferior choroidal neovascularization. Age-related macular degeneration (AMD) is a persistent eye disease that can be divided into two types, dry and wet. Most of the diseases start from dry and then develop wet. The main cause of wet macular degeneration is the appearance of macular areas in abnormal blood vessels. Scars, patient's central vision can quickly deteriorate, and even blindness in the short term. The disease has not yet been proven to be an effective treatment, but the new Visudyne photodynamic therapy can control the disease of 80% of the patients. This product is a substance that selectively accumulates in abnormal new blood vessels. It can be activated by non-thermal laser after intravenous injection. It can destroy abnormal blood vessels without affecting other healthy tissues in the macular area. A specially designed laser is used in this therapy, which produces the low-intensity 689-nanometer non-thermal light needed to activate the drug. ^[3]

The mechanism of action of verteporfin :

Vetiporfin treatment is a two-step treatment that requires injections of Vetiporfin and a non-pyrogenic red light source.

Verteporfin is mainly transported by lipoproteins in the plasma. In an aerobic environment, once activated by light, vertipofen produces highly active, short-lived monooxygen and active oxygen free radicals. Light-activated Vetiporfin can damage local neovascular endothelial cells and cause vessel closure. It is known that damaged endothelial cells can release procoagulant and vasoactive factors through the lipoxygenase (leukotrienes) and cyclooxygenase (arachidoids such as thromboxane) pathways, causing platelet aggregation and fibrin clot formation and vasoconstriction. Verteporfin accumulates mainly in new blood vessels, including choroidal neovascularization. However, animal tests have shown that vertepofen also appears in the retina. Therefore, retinal damage also occurs during photodynamic therapy, including retinal pigment epithelial cells and the outer nuclear layer. In humans, the efficacy of verteporfin therapy in causing temporary closure of choroidal neovascularization (CNV) has been confirmed by fluorescence angiography. ^[4]

Vetopofen Toxicology Study

Carcinogenicity, teratogenicity, and effects on reproductive function: There are currently no studies on the carcinogenicity of vertepofen.

It has been reported that photodynamic therapy (PDT) can cause DNA damage, including DNA strand breaks, the emergence of base-sensitive sites, DNA degradation and DNA-protein cross-linking, which can cause chromosomal aberrations, sister chromatid exchange (SCE), and mutation. In addition, after applying other photodynamic therapy drugs, the chance of sister chromatid exchange between Chinese hamster ovary (CHO) cells irradiated with visible light and Chinese hamster lung fibroblasts irradiated with near-ultraviolet light increased. Cell mutations and DNA-protein cross-linking increase, DNA chain breaks increase in human malignant cervical cancer cells, but not in normal cells. In the last few systems, verteporfin was not evaluated. The potential hazards of PDT treatment drugs on DNA damage to humans are unclear.

Vetepofen was administered intravenously 10 mg / kg daily to rats (to male and female rats, respectively, according to AUCinf value, approximately 60 and 40 times the dose of human 6 mg / exposure dose), no male was observed Or the effect of female rats' reproductive capacity. ^[4]

Verteporfin pharmacokinetics

After intravenous infusion of verteporfin, verteporfin is cleared as a secondary index with a terminal elimination half-life of approximately 5-6 hours. When the dose is between 6-20 mg / , both the exposure and the maximum plasma concentration are proportional to the injected dose. In a certain dose range, the pharmacokinetic parameters of the drug are not affected by gender.

Verteporfin is derived from phenylporphyrin, the end product of liver and plasma esterase metabolism, to bisacid. The NADPH-dependent liver enzyme system (including the cytochrome P450 isoenzyme) does not participate in verteporfin metabolism. The drug is excreted in the feces, and less than 0.01% of the drug dose can be found in the urine.

In a study of patients with mild hepatic insufficiency (two abnormal liver function indexes at the time of enrollment), AUC and Cmax were not significantly different from those in the control group, but the half-life was significantly longer, about 20%. ^[4]

Verteporfin indications

Verteporfin therapy is suitable for patients with secondary to age-related macular degeneration, pathological myopia, or suspicious ocular cytoplasmosis, which are typically dominated by concave central choroidal neovascularization.

There is no sufficient evidence to support verteporfin therapy in patients with occult subchoroidal neovascularization. ^[4]

Vertepofen Dosage

Verteporfin treatment is a two-step process that requires both drugs and lasers. The first step was intravenous infusion of Vetiporfin, and the second step was to activate Vetiporfin with a non-thermal diode laser.

The doctor needs to check the patient every 3 months, and should repeat the treatment if there is a choroidal neovascularization in fluorescein angiography.

Vertipofen lesion size determination

The maximum linear distance (GLD) of the lesion was determined by fluorescence angiography and color fundus image. Various typical and occult CNVs, bleeding and / or fluorescent obstruction, and any serous detachment of the retinal pigment epithelium should be determined. A 2.4-2.6x color fundus camera is recommended. The GLD of the lesion on the fluorescent angiogram must be corrected by the camera magnification to obtain the GLD of the lesion on the retina.

Vertepofen Spot Size Determination

The size of the treatment spot should be 1000 m larger than the GLD of the lesion on the retina, with a margin of 500 m to ensure complete coverage of the lesion. The maximum treatment spot for clinical research is 6400 m.

The nasal margin of the treatment spot must be at least 200um from the temporal side of the optic papilla, even if this causes insufficient CNV photocoagulation within 200um of the optic nerve.

Vertepofen Vertepofen Usage

Each vertepor was prepared with 7ml of sterile injection water into a 7.5ml injection with a concentration of 2mg / ml. The configured solution must be stored in a light-shielded state. And use within 4 hours. It is recommended to observe whether the configured solution is precipitated or discolored before injection. The configured solution is a dark green transparent liquid.

Prepare verteporfin at a dose of 6mg / body surface area, and dissolve it in 5% glucose-soluble injection to make a 30mL solution. Complete the intravenous infusion with a suitable syringe pump and filter at a rate of 3 mL per minute in 10 minutes. A 1.2 m filter is used in clinical research.

Pay attention to prevent the injection of local drug solution extravasation. When it happens, pay attention to the local injection protection (see Cautions).

Verteporfin laser treatment

Fifteen minutes after the start of the infusion, the patient was irradiated with a 689 nm laser.

The degree of photoactivation of verteporfin is determined by the total amount of laser light received. When treating choroidal neovascularization, a laser dose of 50 J / cm and a laser intensity of 600 mW / cm are recommended for the lesion. This dose was irradiated in 83 seconds.

The laser dose, laser intensity, magnification of the ophthalmoscope and the setting of the focal length are all important parameters for reasonable laser treatment to form an ideal laser spot. See the laser system operation manual for specific settings and operations.

The laser system must be able to produce light with a constant energy at a wavelength of 689 ± 3nm. The laser passes through the optical fiber, slit lamp and ophthalmoscope lens with a certain magnification to form a single circular spot on the retina.

The following laser systems have been proven to be compatible with Vertepofen, which can produce light with a constant energy at a wavelength of 689 ± 3nm.

· Opal Photoactivator laser console and modified physician LinkLink adapter produced by Lumenis Inc, Santa Clara, CA.

· VISULAS 690s laser and VISULINK PDT / U adapter produced by Carl Zeiss Inc., Thornwood, NY.

Vertepofen simultaneous treatment of both eyes

Controlled studies allow only one eye to be treated per patient. If both eyes are suitable for treatment, the doctor should weigh the advantages and disadvantages of simultaneous treatment of both eyes. If the patient has a previous history of monotherapy with verteporfin and the safety of the treatment has been proven, a single injection of verteporfin can be used to treat both eyes. Fifteen minutes after initiation, first treat the eye that progresses faster. Immediately after the first eye was irradiated, the laser parameters of the second eye were adjusted, and the same laser dose and intensity as those of the first eye were used, and the treatment was started no later than 20 minutes after the start of the infusion.

If the patient has a lesion that can be treated with both eyes for the first time, there is no previous history of treatment with verteporfin, and it is best to treat the eye with faster progress. If there is no obvious safety problem 1 week after the treatment of the first eye, the treatment scheme of the first eye can be used, and then the infusion of verteporfin is used for the treatment of the second eye. Examine the eyes about three months later. If the lesions in both eyes leak, the treatment needs to be repeated and you can reinject the verteporfin for treatment. ^[4]

Verteporfin contraindications

Vertepofen treatment is contraindicated in patients with porphyria and those who are allergic to any of the ingredients in this product. ^[4]

Vetiporfin adverse reactions:

The most commonly reported adverse events of verteporfin therapy were headaches, local reactions to injections (including extravasation and rashes), and visual impairments (blurred vision, decreased visual acuity, and visual field defects). These events occur in approximately 10-30% of patients. The following adverse events are arranged according to each system of the body and are the most common response to verteporfin treatment. The incidence is higher than in the placebo group and occurs in 1-10% of patients:

Eyes: Blepharitis, cataracts, conjunctivitis / conjunctival congestion, dry eyes, itchy eyes, severe vision loss with or without subretinal or vitreous hemorrhage.

Systemic: Weakness, back pain (mainly during drug infusion), fever, flu-like syndrome, photosensitivity.

Cardiovascular system: atrial fibrillation, hypertension, peripheral vascular abnormalities, varicose veins.

Skin: Eczema.

Digestive system: constipation, gastrointestinal cancer, nausea.

Blood / lymphatic system: anemia, decreased white blood cell count, increased white blood cell count.

Liver: abnormal liver function tests.

Metabolism / nutrition: proteinuria, elevated creatinine.

Skeletal muscle: joint pain, arthropathy, muscle weakness.

Nervous system: loss of sensation, sleep disturbance, dizziness.

Respiratory system: cough, pharyngitis, pneumonia.

Special sensations: cataract, hearing impairment, diplopia, tearing disorder.

Urinary system: prostate disorders.

Severe vision loss has been reported in 1-5% of patients within 7 days of treatment, which is equivalent to a loss of vision of 4 lines or more. Some patients recover partially. Photosensitivity usually occurs when the skin is exposed to sunlight after treatment, with skin burns as the manifestation. The incidence of back pain was higher in the verteporfin-treated group, which occurred mainly at the time of infusion.

The following adverse events have a low incidence in clinical studies (<1%) or appear in the clinical application process. They are derived from spontaneous reports, and the sample size of the reported source population is unknown. The classification of these adverse events is based on a number of factors, such as their severity and frequency of reporting, which may be related to the treatment of vertepofen or a sum of the above:

Eye: retinal detachment (non-porous), no perfusion of retina or choroidal blood vessels.

Non-ocular events: chest pain or musculoskeletal pain during infusion, allergic reactions (which can be severe), syncope, severe allergic reactions with dyspnea and flushing, and vascular-vagus nerve reactions. ^[4]

Vertiperfin notes:

Verteporfin warning

Patients treated with verteporfin remain photosensitive within 48 hours of drug infusion

Within 48 hours of treatment, patients should avoid direct exposure of the skin or eyes to sunlight or strong indoor light sources. If patients need emergency surgery within 48 hours of treatment, most body tissues should be protected from strong light as much as possible.

If the patient's vision is severely reduced by 4 or more lines within a week after treatment, the treatment cannot be repeated, at least after the vision has fully recovered to the preoperative level and the treating physician fully considers the advantages and disadvantages of repeated treatment.

The application of mismatched lasers does not provide the conditions required for photoactivation of vertepofen, which may result in incomplete treatment due to incomplete activation of vertepofen, or excessive treatment of vertepofen or damage to surrounding normal tissues.

Vertepofen general considerations

To avoid extravasation of medicinal fluid during infusion of Vetepofen, precautions include, but are not limited to the following:

Establish a venous channel before initiating infusion of verteporfin, and always pay attention to the patency of the channel.
Due to the fragility of the vein wall in some elderly patients, try to choose the largest vein in the arm, such as anterior elbow vein infusion.
Avoid using small dorsal veins.

If extravasation occurs, the infusion must be stopped immediately and applied cold (see Warnings).

Vetepofen should be used with caution in patients with moderate to severe hepatic impairment or biliary obstruction, as there is no clinical experience in treating these patients.

There are no relevant clinical data on the use of verteporfin in anesthesia patients. Injecting 10 or more doses of sedated or anesthetized guinea pigs, verteporfin can cause severe hemodynamic disorders, including death, which may be the result of complement activation. If antihistamine treatment is performed in advance, this phenomenon can be alleviated or eliminated, and similar behavior is not seen in conscious and sedated guinea pigs. In human blood, verteporfin can cause a concentration-dependent complement activation response in vitro. At a concentration of 10 ug / mL (approximately 5 times the patient's expected blood concentration), mild to moderate complement activation occurred. At a concentration of 100 ug / mL, significant complement activation occurred. Symptoms (chest pain, syncope, dyspnea, and flushing) consistent with complement activation occurred in less than 1% of patients treated with verteporfin. Therefore, patients should be closely monitored during the infusion of verteporfin.

Information for patients with Vertepofen

Patients receiving verteporfin will experience transient photosensitivity after infusion. Patients should wear a cuff to remind them to avoid direct sunlight for 5 days of treatment. At this stage, unprotected skin, eyes, or other organs should be protected from direct sunlight or strong indoor light sources. Strong light sources include, but are not limited to: solarium, high-power halogen lights, strong light in operating rooms and dental clinics. Verteporfin for 5 days continuously but also to avoid some of the light emitted medical equipment, such as a pulse oximeter.

If the patient after the first 5 days of treatment must go outdoors, must wear protective clothing during the day, wear sunglasses to protect all of the skin and eyes. Ultraviolet protective agents are not effective in preventing photosensitivity, as skin residual drugs can be activated by visible light.

Patients should also not be completely dark, and patients should be encouraged to expose their skin to the surrounding room light, which can inactivate skin residual drugs through a photobleaching process. ^[4]

Vetepofen for pregnant and lactating women

Verteporfin pregnancy

Rat fetuses were given verteporfin 10 mg / kg / day intravenously during organogenesis (in female rats, according to the AUCinf value, approximately 40 times the human 6 mg / exposure dose), showing no eye deformities / a small increase in the incidence of eye deformity. Rat fetus was given verteporfin 25 mg / kg / day (in female rats, according to AUCinf value, approximately 125 times the dose of human 6 mg / exposure), showing deformed ribs, no eye deformities / small eye deformities increased incidence

During the organogenesis of gestational rabbits, verteporfin 10 mg / kg / day was given intravenously, and there was a decrease in weight gain and a decrease in food intake. The NOAEL for maternal toxicity is 3 mg / kg / day (approximately 7 times the human exposure based on body surface area of 6 mg / ). Teratogenicity did not occur in rabbits injected at a dose of 10 mg / kg / day.

Currently there is no study on the full, well-controlled pregnant women. Only when the drug is much higher than the possible benefits of risk to the fetus brought before considering treatment of this product during pregnancy.

Verteporfin breast-feeding women

It is not clear whether verteporfin for injection into breast milk. Because many drugs into breast milk of lactating women were verteporfin therapy must be careful. ^[4]

Verteporfin medication for the elderly

In clinical studies of the efficacy of verteporfin, approximately 90% of patients treated with verteporfin are over 65 years old. As the age increases, the efficacy gradually decreases. ^[4]

Vetiporfin Drug Interactions:

There are no studies on the drug interactions of verteporfin in humans.

Verteporfin is rapidly excreted primarily through the liver as a prototype. Drug metabolism is limited to liver and plasma esterases. Cytochrome P450 is not involved in the metabolism of verteporfin.

According to the mechanism of action of verteporfin, the combination of many drugs will affect the efficacy of verteporfin. such as:

Calcium channel blockers, polymyxin B or radiotherapy can increase uptake of verteporfin by vascular endothelial cells. Other photosensitizers (e.g., tetracycline, sulfa drugs, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, and griseofulvin) may increase the photosensitivity of the skin. Can eliminate active oxygen species or free radical scavenging compounds such as dimethyl sulfoxide, [beta] carotene, ethanol, formate and mannitol may reduce the activity of verteporfin. Reducing blood clotting, vasoconstriction and platelet aggregation inhibitor drugs such as thromboxane A2, can also reduce the efficacy of verteporfin. ^[4]

Verteporfin medicament excess dimension

The treatment of ocular drugs and / or laser overdose can cause normal retinal vascular perfusion without causing sustained severe vision loss. Drug overdose can prolong the patient's allergy to bright light. It is recommended that once the overdose occurs, the dark time should be prolonged proportionally according to the degree of the patient's overdose. ^[4]

Vetiporfin expert reviews

Before this product was not developed, laser photocoagulation was considered to be the only effective way to treat such diseases. However, in clinical applications, laser photocoagulation can only be applied to a part of patients with CNV beside and outside the fovea, but For these patients, even without treatment, the impact of CNV on vision is limited. In addition, laser photocoagulation itself can damage the retina above the CNV, often resulting in rapid and irreversible vision loss after treatment. Approximately 50% of CNV cases treated with standard laser photocoagulation relapse, and recurrent CNV can cause further visual impairment. The newly launched Visudyne photodynamic therapy allows the remaining 80% of patients to receive appropriate treatment. Among them, 1% to 4% of patients have decreased vision, while most other patients have recovered. In a clinical trial using the drug, patients required an average of 3.4 treatments in the first year. Of the 243 patients with typical wet macular disease treated, vision decline was controlled in 67% of patients, and some of them had more vision. it has been improved. ^[3]