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
Weight
Average: 840.26
Monoisotopic: 839.181629
Chemical Formula
C37H43N5O9PdS
Synonyms
  • Padeliporfin
External IDs
  • WST 1

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
Associated Therapies
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 Cmax of padeliporfin was about 52 mg/L, with a Tmax 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 (Vd) 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 Vd 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.
DrugInteraction
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Padeliporfin.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Padeliporfin.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Padeliporfin.
AlteplaseThe risk or severity of bleeding can be increased when Alteplase is combined with Padeliporfin.
Aminolevulinic acidAminolevulinic acid may increase the photosensitizing activities of Padeliporfin.
AnagrelideThe risk or severity of bleeding can be increased when Anagrelide is combined with Padeliporfin.
AncrodThe risk or severity of bleeding can be increased when Ancrod is combined with Padeliporfin.
AnistreplaseThe risk or severity of bleeding can be increased when Anistreplase is combined with Padeliporfin.
Antithrombin AlfaThe risk or severity of bleeding can be increased when Antithrombin Alfa is combined with Padeliporfin.
Antithrombin III humanThe risk or severity of bleeding can be increased when Antithrombin III human is combined with Padeliporfin.
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Padeliporfin potassiumJQ72VD4XUL698393-30-5AOSMIFSJINLACN-NAEAMVODSA-J
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TookadInjection, powder, for solution183 mgIntravenousSteba Biotech S.A2020-12-18Not applicableEU flag
TookadInjection, powder, for solution366 mgIntravenousSteba Biotech S.A2020-12-18Not applicableEU flag

Categories

ATC Codes
L01XD07 — Padeliporfin
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

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
  1. 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]
  2. 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]
  3. Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]
  4. European Medicines Agency: Tookad (padeliporfin) [Link]
ChemSpider
32699486
Wikipedia
Padeliporfin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentLow Risk Prostate Cancer1
3CompletedTreatmentProstate Cancer2
3RecruitingTreatmentTransitional Cell Cancer of Renal Pelvis and Ureter1
3WithdrawnTreatmentLocalized Prostate Cancer1
2Active Not RecruitingTreatmentLocalized Prostate Cancer1
2CompletedTreatmentProstate Cancer3
1, 2CompletedTreatmentProstate Cancer1
1, 2TerminatedTreatmentRenal Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous183 MG
Injection, powder, for solutionIntravenous366 MG
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
logP-0.19https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804253/
Predicted Properties
PropertyValueSource
Water Solubility0.0344 mg/mLALOGPS
logP2.76ALOGPS
logP-0.27ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)-1.2ChemAxon
pKa (Strongest Basic)6.03ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area215.7 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity193.49 m3·mol-1ChemAxon
Polarizability78.89 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. 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

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Summary of Product Characteristics: TOOKAD (padeliporfin) intravenous injection [Link]

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