Chemical formula: C₁₆₄H₁₆₈N₁₆O₃₂ Molecular mass: 718.794 g/mol PubChem compound: 5362420
Verteporfin, also referred to as benzoporphyrin derivative monoacids (BPD-MA) consists of a 1:1 mixture of the equally active regioisomers BPD-MAC and BPD-MAD. It is used as a light-activated medicinal product (photosensitiser).
By itself, the clinically recommended dose of verteporfin is not cytotoxic. It produces cytotoxic agents only when activated by light in the presence of oxygen. When energy absorbed by the porphyrin is transferred to oxygen, highly reactive short-lived singlet oxygen is generated. Singlet oxygen causes damage to biological structures within the diffusion range, leading to local vascular occlusion, cell damage and, under certain conditions, cell death.
The selectivity of PDT using verteporfin is based, in addition to the localised light exposure, on selective and rapid uptake and retention of verteporfin by rapidly proliferating cells including the endothelium of choroidal neovasculature.
The two regioisomers of verteporfin exhibit similar pharmacokinetic properties of distribution and elimination and thus both isomers are considered verteporfin as a whole from the pharmacokinetic perspective.
Cmax after a 10-minute infusion of 6 and 12 mg/m² body surface area in the target population is approximately 1.5 and 3.5 μg/ml, respectively. The volume of distribution of around 0.60 l/kg at steady state and clearance of around 101 ml/h/kg has been reported following a 10-minute infusion in dose range of 3-14 mg/m². A maximum 2-fold inter-individual variation in plasma concentrations at Cmax (immediately after end of the infusion) and at the time of light administration was found for each verteporfin dose administered.
In whole human blood, 90% of verteporfin is associated with plasma and 10% associated with blood cells, of which very little was membrane associated. In human plasma, 90% of verteporfin is associated with plasma lipoprotein fractions and approximately 6% are associated with albumin.
The ester group of verteporfin is hydrolysed via plasma and hepatic esterases, leading to the formation of benzoporphyrin derivative diacid (BPD-DA). BPD-DA is also a photosensitiser but its systemic exposure is low (5-10% of the verteporfin exposure, suggesting that most of the active substance is eliminated unchanged). In vitro studies did not show any significant involvement of oxidative metabolism by cytochrome P450 enzymes.
Plasma elimination half-life mean values ranged from approximately 5–6 hours for verteporfin.
Combined excretion of verteporfin and BPD-DA in human urine was less than 1%, suggesting biliary excretion.
The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m².
Although mean plasma Cmax and AUC values in elderly patients who received verteporfin are higher than those in young volunteers or patients, these differences are not considered to be clinically significant.
In a study of patients with mild hepatic impairment (defined as having two abnormal hepatic function tests at enrolment), AUC and Cmax were not significantly different from the control group. Half-life, however, was significantly increased by approximately 20%.
No studies on the pharmacokinetics of verteporfin in patients with renal impairment are reported. The renal excretion of verteporfin and its metabolite is minimal (<1% of the verteporfin dose) and thus, clinically significant changes in verteporfin exposure in patients with renal impairment are unlikely.
The pharmacokinetics of verteporfin have been reported to be similar in healthy Caucasian and Japanese men after a dose of 6 mg/m² by a 10-minute infusion.
At the intended dose, pharmacokinetic parameters are not significantly affected by gender.
The acute and light-dependent toxicity of verteporfin was characterised by dose dependent localised deep-tissue damage as a consequence of the pharmacological effect of PDT with verteporfin. Toxicity observed following multiple doses of verteporfin without light was associated mainly with effects on the haematopoietic system. The extent and severity of these effects were consistent among all studies and were dependent on drug dose and dosing duration.
Levels of ocular toxicity in healthy rabbits and monkeys, particularly on the retina/choroid, correlated with medicinal product dose, light dose, and time of light treatment. A retinal toxicity study in healthy dogs with intravenous verteporfin and ambient light on the eye showed no treatment-related ocular toxicity.
In pregnant rats, intravenous verteporfin doses of 10 mg/kg/day (approximately 40-fold human exposure at 6 mg/m² based on AUCinf in female rats) were associated with an increased incidence of anophthalmia/microphthalmia and doses of 25 mg/kg/day (approximately 125-fold the human exposure at 6 mg/m² based on AUCinf in female rats) were associated with an increased incidence of wavy ribs and anophthalmia/microphthalmia. There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day (approximately 20-fold human exposure at 6 mg/m² based on body surface area).
No effect on male or female fertility has been observed in rats following intravenous verteporfin doses of up to 10 mg/kg/day (approximately 60 and 40-fold human exposure at 6 mg/m² based on AUCinf in male and female rats, respectively).
No studies have been conducted to evaluate the carcinogenic potential of verteporfin.
Verteporfin was not genotoxic in the absence or presence of light in the usual battery of genotoxic tests. However, photodynamic therapy (PDT) induces the formation of reactive oxygen species and has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE) and mutations. It is not known how the potential for DNA damage with PDT agents translates into human risk.
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