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General Description:

Padeliporfin, identified by CAS number 759457-82-4, is a notable compound with significant therapeutic applications. Padeliporfin is a water-soluble chlorophyll derivative and cytotoxic photosensitizer used for vascular-targeted photodynamic therapy for malignancies. Vascular-targeted photodynamic therapy (VTP), or vascular targeted photochemotherapy, is a focal treatment for localized prostate cancer. It aims to destroy only cancerous lesions of the prostate, rather than ablating the entire prostate gland. Padeliporfin was first approved by the European Commission on November 10, 2017, for the treatment of low-risk prostate cancer in adults meeting certain clinical criteria.

Indications:

This drug is primarily indicated for: Padeliporfin is indicated for the treatment of adults with previously untreated, unilateral, low-risk, adenocarcinoma of the prostate with a life expectancy greater than or equal to 10 years. Patients must meet the following criteria: clinical stage T1c or T2a; Gleason Score ≤ 6, based on high-resolution biopsy strategies; PSA ≤ 10 ng/mL; and 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Padeliporfin undergoes metabolic processing primarily in: In human liver microsomes and S9 fractions, padeliporfin underwent minimal metabolism. No metabolites of padeliporfin have been identified yet as a radiolabeled study has not been performed. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Padeliporfin are crucial for its therapeutic efficacy: After intravenous bolus injection at a dose of 6 mg/kg into healthy mice, the C_max of padeliporfin was about 52 mg/L, with a T_max of two minutes. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Padeliporfin is an important consideration for its dosing schedule: The estimated half-life is 1.19 hrs ± 0.08 at 4 mg/kg of padeliporfin di-potassium. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Padeliporfin exhibits a strong affinity for binding with plasma proteins: Padeliporfin di-potassium is 99% bound to human plasma proteins. Padeliporfin binds to high-density proteins, including serum albumin, but binds poorly to low-level density lipoproteins and high-density lipoproteins. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Padeliporfin from the body primarily occurs through: In healthy subjects, urinary excretion of padeliporfin was very low, accounting for less than 0.2% of the dose. Fecal elimination is a suspected predominant route of elimination. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Padeliporfin is distributed throughout the body with a volume of distribution of: In healthy men receiving 1.25 to 15 mg/kg of padeliporfin di-potassium, the mean volume of distribution (V_d) ranged from 0.064 to 0.279 L/kg. In patients with localized prostate cancer treated with 2 and 4 mg/kg of padeliporfin di-potassium, the mean V_d ranged from 0.09 to 0.10 L/kg. Upon administration, padeliporfin remain confined within the circulation even at high doses, with minimal extravasation to other tissues. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Padeliporfin is a critical factor in determining its safe and effective dosage: Following administration of 1.25-15 mg/kg of padeliporfin di-potassium in healthy men, clearance of padeliporfin di-potassium ranged from 0.0245 to 0.088 L/h/kg. In patients with localised prostate cancer treated with 4 mg/kg and 2 mg/kg of padeliporfin di-potassium, clearance was 0.04 L/h/kg and 0.06 L/h/kg, respectively. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Padeliporfin exerts its therapeutic effects through: Padeliporfin mediates tumour-specific cytotoxicity. It works to destroy target cells through the release of reactive oxygen species in response to an exposure to laser light radiation delivered at a specific wavelength. Padeliporfin causes vascular shutdown and activation of an immune response in the target tissue. In preclinical studies in animal models, padeliporfin-mediated photosensitization caused occlusion of the full tumour vasculature in a few minutes of treatment. Padeliporfin remains confined within the circulation even at high doses with minimal extravasation: reactive oxygen species generated upon laser activation are contained in the vasculature and do not directly kill tumour cells. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Padeliporfin functions by: Vascular-targeted photodynamic therapy (VTP), or vascular targeted photochemotherapy, is a focal treatment for localized prostate cancer. VTP involves the process of light activation of photosensitizer localized in the target tissue, which produces reactive oxygen species that work to destroy target cells. Padeliporfin is retained within the vascular system. When activated with 753 nm wavelength laser light, padeliporfin triggers a photochemical reaction that generates oxygen radicals (hydroxyl radical, superoxide radical), thereby causing local hypoxia of the target tissue. Nitric oxide radicals are also released, resulting in transient arterial vasodilatation that triggers the release of the vasoconstrictor, endothelin-1. Rapid consumption of the nitric oxide radicals by oxygen radicals leads to the formation of reactive nitrogen species (RNS) including peroxynitrite, in parallel to arterial constriction. Impaired deformability enhances erythrocyte aggregability and formation of blood clots at the interface of the arterial supply of the target tissue, leading to occlusion of the tumour vasculature, or "vascular shutdown." This effect is enhanced by RNS-induced endothelial cell apoptosis and initiation of self-propagated tumour cells necrosis through peroxidation of their membrane. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Padeliporfin is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Chlorophyll, Heterocyclic Compounds, Fused-Ring, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, Palladium, Photoreceptors, Microbial, Photosensitizing Agents, Proteins, Sensitizers Used in Photodynamic/radiation Therapy. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Padeliporfin include:

• logP: -0.19