Temoporfin

Identification

Name
Temoporfin
Accession Number
DB11630
Type
Small Molecule
Groups
Approved, Investigational
Description

Temoporfin is a photosensitizing agent used in the treatment of squamous cell carcinoma of the head and neck [Label]. It was first authorized for market by the European Medicines Agency in October 2001. It is currently available under the brand name Foscan.

Structure
Thumb
Synonyms
  • 2,3-dihydro-5,10,15,20-tetra(m-hydroxyphenyl)porphyrin
  • m-THPC
  • meso-tetrahydroxyphenylchlorin
  • Temoporfin
External IDs
EF-9 / EF9
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FoscanInjection, solution1 mg/mlIntravenousBiolitec Pharma Ltd2001-10-24Not applicableEu
FoscanInjection, solution1 mg/mlIntravenousBiolitec Pharma Ltd2001-10-24Not applicableEu
FoscanInjection, solution1 mg/mlIntravenousBiolitec Pharma Ltd2001-10-24Not applicableEu
Categories
UNII
FU21S769PF
CAS number
122341-38-2
Weight
Average: 680.764
Monoisotopic: 680.242355526
Chemical Formula
C44H32N4O4
InChI Key
LYPFDBRUNKHDGX-LWQDQPMZSA-N
InChI
InChI=1S/C44H32N4O4/c49-29-9-1-5-25(21-29)41-33-13-15-35(45-33)42(26-6-2-10-30(50)22-26)37-17-19-39(47-37)44(28-8-4-12-32(52)24-28)40-20-18-38(48-40)43(36-16-14-34(41)46-36)27-7-3-11-31(51)23-27/h1-17,19,21-24,46-47,49-52H,18,20H2/b41-33-,41-34-,42-35-,42-37-,43-36-,43-38-,44-39-,44-40-
IUPAC Name
3-[7,12,17-tris(3-hydroxyphenyl)-21,22,23,24-tetraazapentacyclo[16.2.1.1³,⁶.1⁸,¹¹.1¹³,¹⁶]tetracosa-1,3,5,7,11(23),12,14,16,18(21),19-decaen-2-yl]phenol
SMILES
OC1=CC=CC(=C1)C-1=C2\CCC(=N2)\C(=C2/N\C(\C=C2)=C(/C2=N/C(/C=C2)=C(\C2=CC=C\-1N2)C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1

Pharmacology

Indication

For use in the treatment of patients with advanced squamous cell carcinoma of the head and neck failing standard therapies and who are unsuitable for radiotherapy, surgery, or systemic chemotherapy [Label].

Associated Conditions
Pharmacodynamics

Temoporfin is a photosensitizing agent [Label]. It enters cancer cells and is activated via light to produce reactive species which destroy the cell.

Mechanism of action

Temoporfin is excited from ground state to the first excited singlet state by the application of 652 nm light [4, 2]. It is then thought to undergo intersystem crossing to an excited triplet state which is longer lived and able to interact with surrounding molecules [2]. It is then thought to produce cytotoxic species by either a Type I or Type II reaction typical of agents used in photodynamic therapy. Type I involves either hydrogen abstraction of electron transfer from the excited photosensitizer to a substrate molecule to produce free radicals or radical ions. Type II reactions involve a similar reaction with oxygen as the substrate to produce reactive oxygen species. These reactive products cause oxidative damage to the cancer cell resulting in cell death.

There is evidence that photodynamic therapy with Temoporfin activates macrophages and increases phagocytosis [3]. These activated macrophages also produce more tumour necrosis factor-α (TNF-α) and nitric oxide (NO). It is thought that this increase in macrophage activity contributes to the efficacy of therapy through phagocytosis of cancer cells and increased cell death signalling though TNF-α. The increase in NO production likely contributes to oxidative damage through reactive nitrogen species.

Absorption

Tmax is 2-4 h after intravenous administration [Label]. Plasma concentration initially decreases rapidly then slowly rises to reach peak serum concentration [4].

Volume of distribution

The volume of distribution is 0.34-0.46 L/kg [4]. Temoporfin is known to distribute into the tissues and preferentially collects in tumour tissue.

Protein binding

Temoporfin is 85-88% bound to plasma proteins [Label]. Temoporfin initially binds and aggregates to an unknown high density protein [1]. This makes up about 70% of the bound drug immediately after administration. The remainder is bound to plasma lipoproteins with 22% bound to high density lipoprotein (HDL), 4% bound to low density lipoprotein (LDL), and 4% bound to very low density lipoprotein (VLDL). Within 24 hours after administration, Temoporfin undergoes redistribution to lipoproteins with about 73% bound to HDL, 8% bound to LDL, and 3% bound to VLDL. Only 17% remains bound to the unknown high density protein after redistribution.

Metabolism

The exact metabolic reactions Temoporfin undergoes are unknown. The drug metabolites have been identified as conjugates but specific information is unavailable.

Route of elimination

Data on elimination in humans is limited [Label]. Animal data indicates Temoporfin is eliminated solely by the liver with two conjugated metabolites being excreted through bile. No enterohepatic recirculation has been observed with these metabolites.

Half life

Terminal plasma half life is 65 h [Label]. Elimination of Temoporfin is bi-exponential with the intial phase having a half-life of 30 h and a terminal half-life of 61-88 h [4].

Clearance

Temoporfin is cleared at a rate of 3.9-4.1 mL/h/kg [4].

Toxicity

Mice and rats experienced swelling and darkening of exposed tissue at single dosages of >0.85 mg/kg under normal lighting [4]. Systemic toxicity presented as reduced red blood cell and platelet counts and increased white blood cell counts and liver and spleen weights. Skin inflammation, pycnotic spermatocytes and increased extramedullary haematopoiesis in spleen and the lymph nodes was also observed. Under low-light conditions mild phototoxicity was observed only at high doses.

Severe phototoxicity has been seen in rats with repeated doses of up to 1 mg/kg/day under normal lighting [4]. This effect is less severe under low-light conditions. Two weeks of repeated doses of 0.5-0.6 mg/kg/day resulted in inflammation of the injection site and skin in rats. At 0.3 mg/kg/day under low-light in rats, the only effect seen was an increase in white blood cell counts.

In beagle dogs recieving repeated doses of up to 3mg/kg/day under low-light conditions, reddening of the skin and injection site inflammation was seen [4]. Serious injection site damage was observed.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
Porfimer sodiumTemoporfin may increase the photosensitizing activities of Porfimer sodium.
VerteporfinTemoporfin may increase the photosensitizing activities of Verteporfin.
Food Interactions
Not Available

References

General References
  1. Hopkinson HJ, Vernon DI, Brown SB: Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma. Photochem Photobiol. 1999 Apr;69(4):482-8. [PubMed:10212581]
  2. Sharman WM, Allen CM, van Lier JE: Photodynamic therapeutics: basic principles and clinical applications. Drug Discov Today. 1999 Nov;4(11):507-517. [PubMed:10529768]
  3. Coutier S, Bezdetnaya L, Marchal S, Melnikova V, Belitchenko I, Merlin JL, Guillemin F: Foscan (mTHPC) photosensitized macrophage activation: enhancement of phagocytosis, nitric oxide release and tumour necrosis factor-alpha-mediated cytolytic activity. Br J Cancer. 1999 Sep;81(1):37-42. doi: 10.1038/sj.bjc.6690648. [PubMed:10487610]
  4. EMA: Temoporfin Scientific Discussion [Link]
External Links
KEGG Drug
D06066
KEGG Compound
C11730
ChemSpider
54754
ChEBI
9437
ChEMBL
CHEMBL500576
Wikipedia
Temoporfin
ATC Codes
L01XD05 — Temoporfin
FDA label
Download (314 KB)
MSDS
Download (23.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1SuspendedTreatmentRecurrent Non-Small Cell Lung Carcinoma / Stage IIA Non-Small Cell Lung Carcinoma / Stage IIB Non-Small Cell Lung Carcinoma / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIb Non-small Cell Lung Cancer1
1WithdrawnTreatmentCarcinoma, Non-Small-Cell-Lung1
2RecruitingTreatmentCholangiocarcinomas / Hilar Cholangiocarcinoma / Tumors1
2TerminatedTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2Unknown StatusTreatmentHead and Neck Carcinoma1
2Unknown StatusTreatmentNasopharyngeal Carcinoma1
2Unknown StatusTreatmentNon-curative Resectable Bile Duct Carcinoma1
Not AvailableWithdrawnTreatmentRecurrent Squamous Cell Carcinoma of the Lip and Oral Cavity / Recurrent Squamous Cell Carcinoma of the Oropharynx / Recurrent Verrucous Carcinoma of the Oral Cavity / Stage I Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage I Squamous Cell Carcinoma of the Oropharynx / Stage I Verrucous Carcinoma of the Oral Cavity / Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity / Stage II Squamous Cell Carcinoma of the Oropharynx / Stage II Verrucous Carcinoma of the Oral Cavity / Tongue Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous1 mg/ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP9.21ChemAxon
pKa (Strongest Acidic)9.12ChemAxon
pKa (Strongest Basic)5.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area138.28 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity201.34 m3·mol-1ChemAxon
Polarizability76.61 Å3ChemAxon
Number of Rings9ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Carriers

1. High density lipoprotein
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
References
  1. Hopkinson HJ, Vernon DI, Brown SB: Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma. Photochem Photobiol. 1999 Apr;69(4):482-8. [PubMed:10212581]
2. Low density lipoprotein
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
References
  1. Hopkinson HJ, Vernon DI, Brown SB: Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma. Photochem Photobiol. 1999 Apr;69(4):482-8. [PubMed:10212581]
3. Very low density lipoprotein
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
References
  1. Hopkinson HJ, Vernon DI, Brown SB: Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma. Photochem Photobiol. 1999 Apr;69(4):482-8. [PubMed:10212581]

Drug created on October 17, 2016 15:26 / Updated on December 16, 2018 06:58