Chemical formula: C₃₇H₅₉N₅O₉PdS Molecular mass: 840.26 g/mol
Padeliporfin is retained within the vascular system. When activated with 753 nm wavelength laser light, padeliporfin triggers a cascade of pathophysiological events resulting in focal necrosis within a few days. Activation within the illuminated tumour vasculature, generates oxygen radicals (•OH, •Ο2-) causing local hypoxia that induces the release of nitric oxide (•NO) radicals. This results in transient arterial vasodilatation that triggers the release of the vasoconstrictor, endothelin-1. Rapid consumption of the •NO radicals, by oxygen radicals, leads to the formation of reactive nitrogen species (RNS) (e.g. peroxynitrite), in parallel to arterial constriction. In addition, impaired deformability is thought to enhance erythrocyte aggregability and formation of blood clots at the interface of the arterial supply (feeding arteries) and tumour microcirculation, results in occlusion of the tumour vasculature. This is enhanced by RNS-induced endothelial cell apoptosis and initiation of self-propagated tumour cells necrosis through peroxidation of their membrane.
In patients with localised prostate cancer who received Padeliporfin-VTP, necrosis was observed by Magnetic Resonance Imaging (MRI) at day 7. There was a correlation between the total energy delivered and the volume of necrosis observed at day 7. The LDI corresponds to the ratio of the cumulative length of illuminated fibre tips (cm) to the volume (cc) of the targeted zone to be treated. The targeted zone corresponds to the lobe containing the positive biopsies. Its volume is measured after prostate delineation using the treatment guidance software. In Phase II studies, treatment conditions corresponding to an LDI ≥1 were associated with a mean rate of necrosis of the targeted zone at day 7 of 89% ± 20.75 for unilateral treatment. An LDI ≥1 appeared to be associated with a greater volume of necrosis on Day 7 MRI and greater share of patients with negative biopsy at 6 months compared with an LDI <1 (see section 4.2).
There was no significant correlation between the percentage of prostate necrosis on Day 7 MRI and the likelihood of a negative prostate biopsy at follow-up.
The pharmacokinetic properties of padeliporfin were studied in 42 healthy human male subjects (without photoactivation) and in 70 patients with localised prostate cancer (after photoactivation).
In healthy human male subjects, the mean volume of distribution ranged from 0.064-0.279 L/kg, for posologies from 1.25 to 15 mg/kg of padeliporfin di-potassium indicating distribution into extracellular fluid. A similar mean distribution volume was seen in patients with localised prostate cancer treated with 2 and 4 mg/kg of padeliporfin di-potassium (0.09-0.10 L/kg respectively). Padeliporfin di-potassium is highly bound to human plasma proteins (99%).
In vitro studies indicate that padeliporfin is unlikely to be a substrate of OATP1B1, OATP1B3, OCT1, OATP2B1, P-gp, BCRP, MRP2 or BSEP hepatic uptake transporters.
Minimal metabolism of padeliporfin was observed in in vitro metabolism studies in human liver microsomes and S9 fractions. No metabolites of padeliporfin were observed in these studies.
No in vitro or in vivo studies have been conducted with radiolabelled padeliporfin. Therefore, the possibility for some in vivo metabolism of padeliporfin cannot be fully excluded.
In vitro studies indicate that padeliporfin is unlikely to be an inhibitor of CYP450 enzymes.
In vitro studies indicate that padeliporfin does not inhibit P-gp, OAT1, OAT3, OCT2, OCT1, BCRP and BSEP but it could inhibit both OATP1B1 and OATP1B3 transporters.
Clearance of padeliporfin di-potassium in healthy male subjects treated from 1.25 mg/kg up to 15 mg/kg of padeliporfin di-potassium ranged from 0.0245 to 0.088 L/h/kg. Based on popPK analysis the estimated half-life is 1.19 h ± 0.08 at 4 mg/kg of padeliporfin di-potassium. A similar mean clearance range was seen in patients with localised prostate cancer treated with 4 mg/kg and 2 mg/kg of padeliporfin di-potassium (0.04-0.06 L/h/kg respectively). Urinary excretion of padeliporfin in healthy human subjects was very low (<0.2% of the dose). Taking into account its molecular mass and the very low urinary excretion of the molecule, faecal elimination is the most probable route of elimination in human.
Very few patients aged over 75 years were enrolled into studies where pharmacokinetic measurements were taken so it is not known if there is a difference in these older patients compared to patients less than 75 years of age.
In healthy human male subjects, the Cmax was shown to be linear from 1.25 mg/kg to 15 mg/kg of padeliporfin di-potassium, covering the therapeutic range.
The effects of age, weight and race were investigated in healthy volunteers and patients.
The results of the population PK study showed that age, race, health status and markers of hepatic function were unlikely to have a substantial and biologically significant impact on the pharmacokinetics of padeliporfin.
The body weight of patients (range 60-120 kg) presented a minor impact on the padeliporfin pharmacokinetic parameters for doses up to 5 mg/kg of padeliporfin di-potassium.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
In vitro genotoxicity testing identified padeliporfin as having weak potential to induce clastogenicity when illuminated by ultraviolet (UV); this correlates with the mechanism of action (formation of reactive oxygen species).
Padeliporfin was shown to be cytotoxic in the presence of UVA irradiation (in vitro) and considered phototoxic in the guinea pig (in vivo).
Carcinogenicity and reproductive toxicity studies have not been conducted with padeliporfin.
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