Pafolacianine

Identification

Summary

Pafolacianine is an optical imaging agent indicated in adult patients with ovarian cancer as an adjunct for intraoperative identification of malignant lesions.

Generic Name

Pafolacianine

DrugBank Accession Number

DB15413

Background

Pafolacianine, or OTL38, is a folate analogue conjugated with a fluorescent dye that absorbs light in the near-infrared (NIR) spectrum ³ within a range of 760 nm to 785 nm, with a peak absorption of 776 nm. It emits fluorescence within a range of 790 nm to 815 nm with a peak emission of 796 nm.⁵ The longer wavelength allows for deeper penetration of the fluorescent light through tissues for better imaging and detection of tumours. Pafolacianine targets the folate receptor alpha (FRα) which is upregulated in numerous epithelial malignancies.³

On November 29, 2021, the FDA approved pafolacianine as an adjunct imaging agent for intraoperative identification of malignant lesions in adult patients with ovarian cancer.⁵ It is currently under investigation for use in FRα-positive pituitary adenoma, lung cancer,⁴ and renal-cell carcinoma, which is thought to be the second-highest folate receptor-expressing cancer.³

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Pafolacianine (DB15413)

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Weight

Average: 1326.49
Monoisotopic: 1325.353776429

Chemical Formula

C₆₁H₆₇N₉O₁₇S₄

Synonyms

Not Available

External IDs

• OTL 0038
• OTL 38
• OTL-0038
• OTL0038
• OTL38

Pharmacology

Indication

Pafolacianine is an optical imaging agent indicated in adult patients with ovarian cancer as an adjunct for intraoperative identification of malignant lesions.⁵

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Associated Conditions

• Malignant Lesions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Tumor to background ratios changed with different mass doses studied. High tumor to background ratio was observed with 0.025 mg/kg dose. Pafolacianine exposure-response relationships and the time course of pharmacodynamic responses are unknown.⁵

Mechanism of action

Pafolacianine is consists of folic acid linked by its γ-carboxyl and a short spacer to an indocyanine green-related near-infrared dye called SO456. It is used for intraoperative fluorescence for tumour identification and surgical resection. It targets the folate receptor alpha (FRα), which is often overexpressed in various cancers including ovarian cancer.¹ Pafolacianine binds to FRα-expressing cancer cells with an affinity of ~1 nM and is internalized via receptor-mediated endocytosis to be concentrated in FR-positive cancer tissues.⁵ Pafolacianine absorbs light and in the near-infrared (NIR) region within a range of 760 nm to 785 nm with a peak absorption of 776 nm and, upon excitation, emits fluorescence within a range of 790 nm to 815 nm with a peak emission of 796 nm.⁵

Target	Actions	Organism
AFolate receptor alpha	ligand	Humans

Absorption

The mean C_max of pafolacianine was 59.1 ± 5.94 ng/mL and AUC_inf was 63.6 ± 12.6 ng x hr/mL.⁵

Volume of distribution

The mean volume of distribution (V_z) is 17.1 ± 5.99 L, indicating distribution into tissues.⁵ During intraoperative molecular imaging for surgically resectable pulmonary adenocarcinoma, pafolacianine accumulated in nearly 70% of squamous cell carcinomas.⁴

Protein binding

Plasma protein binding of pafolacianine is 93.7%. No notable partitioning into red blood cells was observed.⁵

Metabolism

The metabolism of pafolacianine is unknown; however, pafolacianine is not metabolized by cytochrome P450 (CYP) enzymes.⁵

Route of elimination

Following a single intravenous infusion of radiolabeled pafolacianine sodium, approximately 35% of the dose was recovered in urine (19.1%) and in feces (15.8%) after approximately 3-5 weeks.⁵

Half-life

The elimination half-life of pafolacianine is 0.44 ± 0.23 hours.⁵

Clearance

The mean plasma clearance is 28.6 ± 4.97 L/hr.⁵

Adverse Effects

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Toxicity

There is limited information on the overdosage profile of pafolacianine.

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Folic acid	Folic acid may decrease effectiveness of Pafolacianine as a diagnostic agent.
Glucarpidase	The serum concentration of the active metabolites of Pafolacianine can be reduced when Pafolacianine is used in combination with Glucarpidase resulting in a loss in efficacy.
Leucovorin	Leucovorin may decrease effectiveness of Pafolacianine as a diagnostic agent.
Levoleucovorin	Levoleucovorin may decrease effectiveness of Pafolacianine as a diagnostic agent.
Levomefolic acid	Levomefolic acid may decrease effectiveness of Pafolacianine as a diagnostic agent.

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Food Interactions

No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Pafolacianine sodium	4HUF3V875C	1628858-03-6	LRVBSDMJFVZFHH-NFVAJSDSSA-J

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cytalux	Injection	3.2 mg/1.6mL	Intravenous	On Target Laboratories, Inc.	2021-11-29	Not applicable

Categories

ATC Codes

V04CX10 — Pafolacianine

• V04CX — Other diagnostic agents
• V04C — OTHER DIAGNOSTIC AGENTS
• V04 — DIAGNOSTIC AGENTS
• V — VARIOUS

Drug Categories

• Compounds used in a research, industrial, or household setting
• Diagnostic Agents
• Diagnostic Uses of Chemicals
• Folic Acid Analogues
• Heterocyclic Compounds, Fused-Ring
• Laboratory Chemicals
• Molecular Probes
• OAT1/SLC22A6 Substrates
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 substrates
• Optical Imaging Agent
• Pteridines
• Pterins

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Phenylalanine and derivatives

Alternative Parents

Hippuric acids / N-acyl-alpha amino acids / Pterins and derivatives / Phenylpropanoic acids / Amphetamines and derivatives / Aminobenzamides / 3-alkylindoles / 1-sulfo,2-unsubstituted aromatic compounds / Benzoyl derivatives / Aniline and substituted anilines / Tertiary alkylarylamines / Phenoxy compounds / Phenylalkylamines / Secondary alkylarylamines / Aminopyrimidines and derivatives / Pyrimidones / Primary aromatic amines / Pyrazines / Organosulfonic acids / Alkanesulfonic acids / Sulfonyls / Vinylogous amides / Heteroaromatic compounds / Amino acids / Secondary carboxylic acid amides / Propargyl-type 1,3-dipolar organic compounds / Monocarboxylic acids and derivatives / Enamines / Azacyclic compounds / Carboxylic acids / Organopnictogen compounds / Hydrocarbon derivatives / Organic salts / Organic oxides / Carbonyl compounds / Organic cations

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Substituents

1-sulfo,2-unsubstituted aromatic compound / 3-alkylindole / 3-phenylpropanoic-acid / Alkanesulfonic acid / Amine / Amino acid / Aminobenzamide / Aminobenzoic acid or derivatives / Aminopyrimidine / Amphetamine or derivatives / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound / Arylsulfonic acid or derivatives / Azacycle / Benzamide / Benzenoid / Benzoic acid or derivatives / Benzoyl / Carbonyl group / Carboxamide group / Carboxylic acid / Enamine / Heteroaromatic compound / Hippuric acid / Hippuric acid or derivatives / Hydrocarbon derivative / Indole or derivatives / Monocarboxylic acid or derivatives / Monocyclic benzene moiety / N-acyl-alpha amino acid or derivatives / N-acyl-alpha-amino acid / Organic 1,3-dipolar compound / Organic cation / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organic salt / Organic sulfonic acid or derivatives / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Organosulfonic acid / Organosulfonic acid or derivatives / Organosulfur compound / Phenoxy compound / Phenylalanine or derivatives / Phenylalkylamine / Primary amine / Primary aromatic amine / Propargyl-type 1,3-dipolar organic compound / Pteridine / Pterin / Pyrazine / Pyrimidine / Pyrimidone / Secondary aliphatic/aromatic amine / Secondary amine / Secondary carboxylic acid amide / Sulfonyl / Tertiary aliphatic/aromatic amine / Tertiary amine / Vinylogous amide

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

F7BD3Z4X8L

CAS number

1628423-76-6

InChI Key

PDXNSXLPXJFETD-DYVQZXGMSA-N

InChI

InChI=1S/C61H67N9O17S4/c1-60(2)46-33-44(90(81,82)83)22-24-49(46)69(28-5-7-30-88(75,76)77)51(60)26-16-38-10-9-11-39(17-27-52-61(3,4)47-34-45(91(84,85)86)23-25-50(47)70(52)29-6-8-31-89(78,79)80)54(38)87-43-20-12-37(13-21-43)32-48(58(73)74)66-56(71)40-14-18-41(19-15-40)63-35-42-36-64-55-53(65-42)57(72)68-59(62)67-55/h12-27,33-34,36,48H,5-11,28-32,35H2,1-4H3,(H9-,62,63,64,66,67,68,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86)/t48-/m0/s1

IUPAC Name

2-[(1E)-2-[(3E)-2-{4-[(2S)-2-[(4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}phenyl)formamido]-2-carboxyethyl]phenoxy}-3-{2-[(2E)-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2,3-dihydro-1H-indol-2-ylidene]ethylidene}cyclohex-1-en-1-yl]ethenyl]-3,3-dimethyl-1-(4-sulfobutyl)-3H-indol-1-ium-5-sulfonate

SMILES

CC1(C)\C(=C/C=C2\CCCC(\C=C\C3=[N+](CCCCS(O)(=O)=O)C4=C(C=C(C=C4)S([O-])(=O)=O)C3(C)C)=C2OC2=CC=C(C[C@H](NC(=O)C3=CC=C(NCC4=CN=C5N=C(N)NC(=O)C5=N4)C=C3)C(O)=O)C=C2)N(CCCCS(O)(=O)=O)C2=C1C=C(C=C2)S(O)(=O)=O

References

General References

1. Shum CF, Bahler CD, Low PS, Ratliff TL, Kheyfets SV, Natarajan JP, Sandusky GE, Sundaram CP: Novel Use of Folate-Targeted Intraoperative Fluorescence, OTL38, in Robot-Assisted Laparoscopic Partial Nephrectomy: Report of the First Three Cases. J Endourol Case Rep. 2016 Nov 1;2(1):189-197. doi: 10.1089/cren.2016.0104. eCollection 2016. [Article]
2. Randall LM, Wenham RM, Low PS, Dowdy SC, Tanyi JL: A phase II, multicenter, open-label trial of OTL38 injection for the intra-operative imaging of folate receptor-alpha positive ovarian cancer. Gynecol Oncol. 2019 Oct;155(1):63-68. doi: 10.1016/j.ygyno.2019.07.010. Epub 2019 Jul 27. [Article]
3. Bahler CD, Maniar V, Marley KN, Kheyfets SV, Shum CF, Sundaram CP: OTL-38-Guided Fluorescent Imaging in Renal Cell Cancer Robotic Partial Nephrectomy. J Endourol B Videourol. 2017 Feb 6;31(3). pii: 10.1089/vid.2016.0068. doi: 10.1089/vid.2016.0068. eCollection 2017. [Article]
4. Predina JD, Newton AD, Xia L, Corbett C, Connolly C, Shin M, Sulyok LF, Litzky L, Deshpande C, Nie S, Kularatne SA, Low PS, Singhal S: An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas. Oncotarget. 2018 Feb 5;9(17):13517-13529. doi: 10.18632/oncotarget.24399. eCollection 2018 Mar 2. [Article]
5. FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]

External Links

ChemSpider

34990487

RxNav

2586857

ChEMBL

CHEMBL4297412

Wikipedia

Pafolacianine

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Diagnostic	Lung Cancer / Lung Neoplasm	1
3	Completed	Other	Ovarian Cancer	1
2	Completed	Diagnostic	Lung Cancer / Lung Neoplasm	1
2	Completed	Other	Ovarian Cancer	1
1	Completed	Diagnostic	Neoplasm	1
1	Completed	Diagnostic	Patients With Suspected Malignancies of the Pituitary Gland	1
1	Recruiting	Diagnostic	A Diagnosis of Any Resectable Lung or Pleural Nodule	1
1	Terminated	Diagnostic	Neoplasm / Pituitary Neoplasms	1
1	Withdrawn	Other	Ovarian Cancer	1
Not Available	Completed	Not Available	Bladder Cancer / Gastric Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	3.2 mg/1.6mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9333270	No	2016-05-10	2033-08-26
US9061057	No	2015-06-23	2033-08-26
US10881747	No	2021-01-05	2033-08-26
US9789208	No	2017-10-17	2033-08-26
US9254341	No	2016-02-09	2033-10-04
US9341629	No	2016-05-17	2033-08-26

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00313 mg/mL	ALOGPS
logP	0.93	ALOGPS
logP	2.26	Chemaxon
logS	-5.6	ALOGPS
pKa (Strongest Acidic)	-2.2	Chemaxon
pKa (Strongest Basic)	2.12	Chemaxon
Physiological Charge	-4	Chemaxon
Hydrogen Acceptor Count	23	Chemaxon
Hydrogen Donor Count	8	Chemaxon
Polar Surface Area	407.48 Å2	Chemaxon
Rotatable Bond Count	25	Chemaxon
Refractivity	355.08 m3·mol-1	Chemaxon
Polarizability	139.21 Å3	Chemaxon
Number of Rings	9	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

Targets

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Details1. Folate receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Ligand

General Function

Receptor activity

Specific Function

Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analo...

Gene Name

FOLR1

Uniprot ID

P15328

Uniprot Name

Folate receptor alpha

Molecular Weight

29818.94 Da

References

1. Randall LM, Wenham RM, Low PS, Dowdy SC, Tanyi JL: A phase II, multicenter, open-label trial of OTL38 injection for the intra-operative imaging of folate receptor-alpha positive ovarian cancer. Gynecol Oncol. 2019 Oct;155(1):63-68. doi: 10.1016/j.ygyno.2019.07.010. Epub 2019 Jul 27. [Article]
2. Shum CF, Bahler CD, Low PS, Ratliff TL, Kheyfets SV, Natarajan JP, Sandusky GE, Sundaram CP: Novel Use of Folate-Targeted Intraoperative Fluorescence, OTL38, in Robot-Assisted Laparoscopic Partial Nephrectomy: Report of the First Three Cases. J Endourol Case Rep. 2016 Nov 1;2(1):189-197. doi: 10.1089/cren.2016.0104. eCollection 2016. [Article]
3. FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]

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Drug created at May 20, 2019 15:26 / Updated at December 17, 2021 21:25