Pafolacianine
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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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Diagnostic agent 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 ligandHumans - 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareFolic 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. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- 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 US
Categories
- ATC Codes
- V04CX10 — Pafolacianine
- 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 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
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
- External Links
- ChemSpider
- 34990487
- 2586857
- ChEMBL
- CHEMBL4297412
- Wikipedia
- Pafolacianine
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 dataNot Available Completed Not Available Bladder Cancer / Gastric Cancer 1 somestatus stop reason just information to hide Not Available Completed Treatment Renal Cell Carcinoma (RCC) 1 somestatus stop reason just information to hide 3 Completed Diagnostic Lung Cancer / Lung Neoplasm 1 somestatus stop reason just information to hide 3 Completed Other Ovarian Cancer 1 somestatus stop reason just information to hide 2 Completed Diagnostic Lung Cancer / Lung Neoplasm 1 somestatus stop reason just information to hide
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 US US9061057 No 2015-06-23 2033-08-26 US US10881747 No 2021-01-05 2033-08-26 US US9789208 No 2017-10-17 2033-08-26 US US9254341 No 2016-02-09 2033-10-04 US US9341629 No 2016-05-17 2033-08-26 US
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
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Ligand
- General Function
- Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells (PubMed:19074442, PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Has high affinity for folate and folic acid analogs at neutral pH (PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release (PubMed:8567728). Required for normal embryonic development and normal cell proliferation (By similarity)
- Specific Function
- folic acid binding
- Gene Name
- FOLR1
- Uniprot ID
- P15328
- Uniprot Name
- Folate receptor alpha
- Molecular Weight
- 29818.94 Da
References
- 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]
- 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]
- FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- FDA Approved Drug Products: CYTALUX (pafolacianine) injection, for intravenous use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- 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