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
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
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

TargetActionsOrganism
AFolate receptor alpha
ligand
Humans
Absorption

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

Volume of distribution

The mean volume of distribution (Vz) 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.
DrugInteraction
Folic acidFolic acid may decrease effectiveness of Pafolacianine as a diagnostic agent.
GlucarpidaseThe 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.
LeucovorinLeucovorin may decrease effectiveness of Pafolacianine as a diagnostic agent.
LevoleucovorinLevoleucovorin may decrease effectiveness of Pafolacianine as a diagnostic agent.
Levomefolic acidLevomefolic acid may decrease effectiveness of Pafolacianine as a diagnostic agent.
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Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Pafolacianine sodium4HUF3V875C1628858-03-6LRVBSDMJFVZFHH-NFVAJSDSSA-J
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CytaluxInjection3.2 mg/1.6mLIntravenousOn Target Laboratories, Inc.2021-11-29Not applicableUS flag

Categories

Drug Categories
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
show 26 more
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
show 54 more
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]
ChemSpider
34990487
RxNav
2586857
ChEMBL
CHEMBL4297412
Wikipedia
Pafolacianine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedDiagnosticLung Cancers / Neoplasms, Lung1
3CompletedOtherOvarian Cancer1
2CompletedDiagnosticLung Cancers / Neoplasms, Lung1
2CompletedOtherOvarian Cancer1
1CompletedDiagnosticPatients With Suspected Malignancies of the Pituitary Gland1
1Not Yet RecruitingScreeningInflammatory Bowel Diseases (IBD) / Rheumatoid Arthritis1
1RecruitingDiagnosticA Diagnosis of Any Resectable Lung or Pleural Nodule1
1RecruitingDiagnosticNeoplastic Disease1
1RecruitingOtherOvarian Cancer1
1TerminatedDiagnosticNeoplastic Disease / Pituitary Neoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous3.2 mg/1.6mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9333270No2016-05-102033-08-26US flag
US9061057No2015-06-232033-08-26US flag
US10881747No2021-01-052033-08-26US flag
US9789208No2017-10-172033-08-26US flag
US9254341No2016-02-092033-10-04US flag
US9341629No2016-05-172033-08-26US flag

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00313 mg/mLALOGPS
logP0.93ALOGPS
logP2.26ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)-2.2ChemAxon
pKa (Strongest Basic)2.12ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count23ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area407.48 Å2ChemAxon
Rotatable Bond Count25ChemAxon
Refractivity355.08 m3·mol-1ChemAxon
Polarizability139.21 Å3ChemAxon
Number of Rings9ChemAxon
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

Targets

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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]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]

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