Padeliporfin

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Identification

Summary

Padeliporfin is a vascular-acting photosensitizer used to treat low-risk prostate cancer in adults.

Generic Name

Padeliporfin

DrugBank Accession Number

DB15575

Background

Padeliporfin is a water-soluble chlorophyll derivative and cytotoxic photosensitizer used for vascular-targeted photodynamic therapy for malignancies.¹ 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.² 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.⁴

Type

Small Molecule

Groups

Approved, Experimental

Structure

Similar Structures

Weight: Average: 840.26
Monoisotopic: 839.181629
Chemical Formula: C₃₇H₄₃N₅O₉PdS

Synonyms

Padeliporfin

External IDs

WST 1

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Pharmacology

Indication

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/cm³.³

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Low risk prostate cancer		••••••••••••	•••••	•••••••••• •••••••••	•••••••••

Associated Therapies

Targeted vascular photodynamic therapy (VTP)

Contraindications & Blackbox Warnings

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Pharmacodynamics

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.¹ In preclinical studies in animal models, padeliporfin-mediated photosensitization caused occlusion of the full tumour vasculature in a few minutes of treatment.²

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.¹

Mechanism of action

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.^1,2

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.³

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.³

Absorption

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.²

Volume of distribution

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.³ Upon administration, padeliporfin remain confined within the circulation even at high doses, with minimal extravasation to other tissues.²

Protein binding

Padeliporfin di-potassium is 99% bound to human plasma proteins.³ Padeliporfin binds to high-density proteins, including serum albumin, but binds poorly to low-level density lipoproteins and high-density lipoproteins.²

Metabolism

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.³

Route of elimination

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.³

Half-life

The estimated half-life is 1.19 hrs ± 0.08 at 4 mg/kg of padeliporfin di-potassium.³

Clearance

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.³

Adverse Effects

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Toxicity

There is no information regarding the LD₅₀ of padeliporfin.

There is limited clinical information on padeliporfin overdose. In clinical studies, healthy subjects were exposed to doses up to 15 mg/kg of padeliporfin di-potassium (corresponding to 13.73 mg/kg of padeliporfin) without light activation and 23 patients have been treated with 6 mg/kg of padeliporfin di-potassium (corresponding to 5.49 mg/kg of padeliporfin) without significant safety issues. However, prolonged photosensitization is possible and precautions against light exposure should be maintained for an additional 24 hours. An overdose of the laser light may increase the risk of undesirable extraprostatic necrosis.³

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Padeliporfin.
Acenocoumarol	The risk or severity of bleeding can be increased when Acenocoumarol is combined with Padeliporfin.
Acetylsalicylic acid	The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Padeliporfin.
Alteplase	The risk or severity of bleeding can be increased when Alteplase is combined with Padeliporfin.
Aminolevulinic acid	Aminolevulinic acid may increase the photosensitizing activities of Padeliporfin.

Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Padeliporfin potassium	JQ72VD4XUL	698393-30-5	AOSMIFSJINLACN-NAEAMVODSA-J

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Tookad	Injection, powder, for solution	366 mg	Intravenous	Steba Biotech B.A.	2020-12-18	Not applicable
Tookad	Injection, powder, for solution	183 mg	Intravenous	Steba Biotech B.A.	2020-12-18	Not applicable

Chemical Identifiers

UNII: EEO29FZT86
CAS number: 759457-82-4
InChI Key: MZRDSGWDVDESRC-VNWQTDIGSA-L
InChI: InChI=1S/C37H45N5O9S.Pd/c1-8-22-17(2)25-16-30-33(21(6)43)19(4)27(40-30)14-26-18(3)23(9-10-31(44)45)35(41-26)24(13-32(46)51-7)36-34(37(47)38-11-12-52(48,49)50)20(5)28(42-36)15-29(22)39-25;/h14-18,22-23H,8-13H2,1-7H3,(H5,38,39,40,41,42,43,44,45,47,48,49,50);/q;+2/p-2/t17-,18+,22-,23+;/m1./s1
IUPAC Name: palladium(2+) (4S,5S,14R,15R)-10-acetyl-4-(2-carboxyethyl)-15-ethyl-2-(2-methoxy-2-oxoethyl)-5,9,14,19-tetramethyl-20-[(2-sulfoethyl)carbamoyl]-21,22,23,24-tetraazapentacyclo[16.2.1.1^{3,6}.1^{8,11}.1^{13,16}]tetracosa-1,3(24),6,8,10,12,16(22),17,19-nonaene-21,23-diide
SMILES: [Pd++].[H][C@]1(C)\C2=C\C3=C(C(C)=O)C(C)=C([N-]3)\C=C3/N=C(/C(/CC(=O)OC)=C4\[N-]\C(=C/C(=N2)[C@]1([H])CC)C(C)=C4C(=O)NCCS(O)(=O)=O)[C@@]([H])(CCC(O)=O)[C@]3([H])C

References

General References

Nogueira L, Tracey AT, Alvim R, Reisz P, Scherz A, Coleman JA, Kim K: Developments in Vascular-Targeted Photodynamic Therapy for Urologic Malignancies. Molecules. 2020 Nov 19;25(22). pii: molecules25225417. doi: 10.3390/molecules25225417. [Article]
Bugaj AM: Vascular targeted photochemotherapy using padoporfin and padeliporfin as a method of the focal treatment of localised prostate cancer - clinician's insight. World J Methodol. 2016 Mar 26;6(1):65-76. doi: 10.5662/wjm.v6.i1.65. eCollection 2016 Mar 26. [Article]
Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]
European Medicines Agency: Tookad (padeliporfin) [Link]

External Links

ChemSpider: 32699486
Wikipedia: Padeliporfin

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
4	Terminated	Treatment	Low Risk Prostate Cancer	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Prostate Cancer	2	somestatus	stop reason	just information to hide
3	Recruiting	Treatment	Transitional Cell Cancer of the Renal Pelvis and Ureter	1	somestatus	stop reason	just information to hide
3	Withdrawn	Treatment	Localized Prostate Cancer	1	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Localized Prostate Cancer	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	183 MG
Injection, powder, for solution	Intravenous	366 MG
Solution	Intravenous	200.1 mg

Prices

Not Available

Patents

Not Available

Properties

State

Liquid

Experimental Properties

Property	Value	Source
logP	-0.19	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804253/

Predicted Properties

Property	Value	Source
Water Solubility	0.0344 mg/mL	ALOGPS
logP	2.76	ALOGPS
logP	-0.27	Chemaxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	-1.2	Chemaxon
pKa (Strongest Basic)	6.03	Chemaxon
Physiological Charge	-2	Chemaxon
Hydrogen Acceptor Count	12	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	215.7 Å²	Chemaxon
Rotatable Bond Count	12	Chemaxon
Refractivity	193.49 m³·mol^-1	Chemaxon
Polarizability	78.89 Å³	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST): Not Available
Spectra: Not Available
Chromatographic Properties: Collision Cross Sections (CCS)
Not Available

Carriers

Details1. Albumin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Binder

General Function: Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function: Antioxidant activity
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Albumin
Molecular Weight: 69365.94 Da

References

Bugaj AM: Vascular targeted photochemotherapy using padoporfin and padeliporfin as a method of the focal treatment of localised prostate cancer - clinician's insight. World J Methodol. 2016 Mar 26;6(1):65-76. doi: 10.5662/wjm.v6.i1.65. eCollection 2016 Mar 26. [Article]

Transporters

Details1. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]

Details2. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

References

Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]

Drug created at November 29, 2019 16:18 / Updated at January 20, 2022 10:18

Padeliporfin

Identification

Structure for Padeliporfin (DB15575)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Carriers

References

Transporters

References

References