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Pralatrexate

HCID 148121
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Basic information

CAS
146464-95-1
Standard SMILES
C#CCC(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
InChIKey
OGSBUKJUDHAQEA-WMCAAGNKSA-N
Molecular formula
C23H23N7O5
Average molar mass
477.5 g/mol
Monoisotopic mass
477.17606686

Overview

Pralatrexate is a pteridine that is the N-4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl derivative of L-glutamic acid. Used for treatment of Peripheral T-Cell Lymphoma, an aggressive form of non-Hodgkins lymphoma. It has a role as an antimetabolite, an antineoplastic agent and an EC 1.5.1.3 (dihydrofolate reductase) inhibitor. It is a N-acyl-L-glutamic acid, a member of pteridines and a terminal acetylenic compound.

Names & identifiers

Preferred name
Pralatrexate
IUPAC
(2S)-2-[[4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl]amino]pentanedioic acid
English name
10-Propargyl-10-deazaaminopterin
Molecular formula
C23H23N7O5
Molecular weight
477.47

Names & synonyms

Pralatrexate146464-95-1Folotyn10-Propargyl-10-deazaaminopterinpralatrexatoHSDB 7786N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acidpralatrexatumDTXSID3048578NSC-754230CHEBI:71223A8Q8I19Q20
Show more names
PdxCS-2172PralatrexatPrelatrexateUnii-A8Q8I19Q20Pralatrexate, >=98%FOLOTYN PRALATREXATEPralatrexate(Folotyn)
(2S)-2-((4-((1RS)-1-((2,4-Diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid(2S)-2-[[4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl]amino]pentanedioic acidDTXCID3028504N-{4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}-L-glutamic acid(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acidL-Glutamic acid, N-(4-(1-((2,4-diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-(2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid(2S)-2-((4-(1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl)benzoyl)amino)pentanedioic acid

Database identifiers

CAS

Properties

Computed structural properties

XLogP
-0.9
Topological polar surface area
207 Ų
Hydrogen bond donors
5
Hydrogen bond acceptors
11
Rotatable bonds
10
Heavy atoms
35
Formal charge
0
Complexity
809

Experimental & physicochemical properties

Color/FormOff-white to yellow solid
Solubility · 2 items

Practically insoluble in shloroform and ethanol

Soluble in aqueous solutions at pH 6.5 or higher

Human Drugs · 2 items

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Dissociation Constants · 2 items

3.25, 4.76, and 6.17

pKa values are 3.25, 4.76, and 6.17

Physicochemical properties

Melting point
215 °C · 215 °C(dec.)
Density
1.471 · 1.471±0.06 g/cm3(Predicted)
storage temp.
2 · 2-8°C
Water Solubility
Insoluble in water
solubility
23.85 mg/mL · ≥23.85 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
pka
3.53 · 3.53±0.10(Predicted)

Safety & regulation

Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.

GHS classification

GHS Classification · 4 items

Danger

H301 (66.7%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P261, P262, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P316, P318, P319, P321, P330, P332+P317, P337+P317, P361+P364, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard information

FDA Requirements · 1 item

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including pralatrexate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Hazard Classes and CategoriesAcute Tox. 3 (66.7%)
Shipment Methods and Regulations · 1 item

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Safety & protection

Chemistry & industry

Pharmacology

ATC Code · 2 items

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Protein BindingThe protein binding of pralatrexate is approximately 67% in vitro.
Pharmacodynamics · 1 item

Pralatrexate is a folate analog that inhibits folate metabolism, thus impeding the synthesis of amino acids and nucleic acid. Additionally, pralatrexate also competes for enzymatic processing by folyopolyglutamate synthase (FPGS)with folate to increase cellular retention. Compared to methotrexate, pralatrexate binds to the reduced folate carrier protein-1 (RFC-1) for cellular uptake with 10-times the affinity and is a more potent substrate for FPGS. The K<sub>m</sub> value for RFC-1 was calculated to be 0.3 μmol/L and 4.8 μmol/L for pralatrexate and methotrexate respectively, while the K<sub>m</sub> value for FPGS was estimated to be 5.9 and 32.3 µmol/l for pralatrexate and methotrexate respectively. As a result, pralatrexate is more cytotoxic and better retained in cancer cells. Due to its anti-folate activity, pralatrexate's main toxicity is manifested as mucositis that can require dose interruption or reduction. In 5 patients with non-small-cell lung carcinoma receiving a supratherapeutic dose of 230 mg/m<sup>2</sup>, the mean change from pre-injection QTcF interval at the end of infusion was 6.1 ms (90%CI: -0.6, 12.7), and at 1-hour post-injection was 7.8 ms (90%CI: 3.0, 12.6). However, no patient exceeded a QTcF of 470 msec and exhibited an absolute increase from baseline in QTcF exceeding 30 msec. As well, the study dose far exceeded the target dose for patients with peripheral T-cell lymphoma and pralatrexate does not inhibit the human ether-a-go-go-related gene (hERG) K<sup>+</sup> channel. Therefore, pralatrexate uses are unlikely to cause cardiac repolarization delays..

Mechanism of Action · 3 items

Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase (DHFR) selectively in cancer cells overexpressing the reduced folate carrier protein-1 (RFC-1). Folate is a water-soluble vitamin required for DNA synthesis and maintenance as well as DNA, RNA, and protein methylation. As cancer cells are rapidly replicating, they require a lot of folates to accommodate an accelerated cell division and DNA and protein modification for cellular transformation. Therefore, interruption with folate metabolism can inhibit tumor growth. Additionally, pralatrexate also undergoes polyglutamylation catalyzed by folyopolyglutamate synthase (FPGS). This reaction both increases cellular retention of pralatrexate for extended drug action and impedes the uptake of folate, also a substrate of FPGS, to further inhibit folate metabolism in cancer cells.

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HRID 2382521 reaction equation
HRID 2382521As reactantuspto-grants-2012_09

Compound notes

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On this pageBasic informationOverviewNames & identifiersPropertiesSafety & regulationChemistry & industryRelated reactionsCompound notes
146464-95-1
PubChem CID
148121
DTXSID
DTXSID3048578
ChEMBL
CHEMBL1201746
ChEBI
CHEBI:71223
UNII
A8Q8I19Q20
EC Number
680-662-0
Nikkaji
J557.257F
form
powder to crystal
color
White to Light yellow
InChIKey
OGSBUKJUDHAQEA-WMCAAGNKSA-N
SMILES
C(O)(=O)[C@H](CCC(O)=O)NC(=O)C1=CC=C(C(CC2C=NC3C(N=2)=C(N)N=C(N)N=3)CC#C)C=C1
NCI Dictionary of Cancer Terms
10 · 10-propargyl-10-deazaaminopterin; Folotyn; PDX; pralatrexate
FDA UNII
8 Q8I19Q20 · A8Q8I19Q20
NCI Drug Dictionary
Folotyn
ATC code
1 BA05 · L01BA05
UNSPSC Code
12352200 · 12352200
NACRES
77 · NA.77
Symbol(GHS)
7 · GHS07,GHS08
Signal word
Warning
Hazard statements
302 · H302-H361
Precautionary statements
201 · P201-P202-P264-P270-P280-P301+P310+P330-P308+P313-P405-P501
WGK Germany
3 · WGK 3
HS Code
2933.59 · 2933.59.5300
Storage Class
11 · 11 - Combustible Solids
Hazard Classifications
2 · Repr. 2
Hazardous Substances Data
146464 · 146464-95-1(Hazardous Substances Data)
Cleanup Methods · 2 items

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

Disposal Methods · 5 items

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/

For more Disposal Methods (Complete) data for Pralatrexate (8 total), please visit the HSDB record page.

Preventive Measures · 5 items

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/

For more Preventive Measures (Complete) data for Pralatrexate (19 total), please visit the HSDB record page.

Personal Protective Equipment (PPE) · 5 items

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

Toxicology

Interactions · 2 items

The effect of co-administration of the uricosuric drug probenecid on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure.

Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole) may result in delayed clearance of pralatrexate.

Hepatotoxicity · 1 item

Pralatrexate is associated with serum enzyme elevations during therapy, but these abnormalities are generally mild and self-limited, rising to above 5 times ULN in 2% to 6% of patients and rarely requiring dose adjustment. No instances of clinically apparent acute liver injury attributed to pralatrexate have been reported in the literature, but monitoring for liver toxicity is recommended. Pralatrexate has not been linked specifically to sinusoidal obstruction syndrome, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which alkylating agents are commonly associated with this complication.

Medical Surveillance · 1 item

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

Human Toxicity Excerpts · 3 items

Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure.

Treatment with FOLOTYN may cause mucositis. If /greater than or equal to/ Grade 2 mucositis is observed, dose should be modified.

FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose.

Drug Induced Liver Injury · 6 items

Drug Induced Liver Injury Rank (DILIrank 2.0)

Pralatrexate

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

Non-Human Toxicity Excerpts · 3 items

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In rabbits, iv doses of 0.03 mg/kg/day (0.36 mg/sq m/day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post implantation loss and a decrease in the total number of live fetuses.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/day (0.36 mg/sq m/day or about 1.2% of the clinical dose on a mg/sq m basis) given on gestation days 7 through 20. Treatment with pralatrexate caused a dose dependant decrease in fetal viability manifested as an increase in late, early and total resorptions. There was also a dose dependant increase in post implantation loss.

/GENOTOXICITY/ Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay.

Antidote and Emergency Treatment · 3 items

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Regulatory information

FDA Requirements · 1 item

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including pralatrexate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Safety data

wgk
WGK 3
hs_code
2933.59.5300
Signal word
Warning
Symbol(GHS)
GHS07,GHS08
Storage Class
11 - Combustible Solids
Hazard statements
H302-H361
Hazard Classifications
Repr. 2
Precautionary statements
P201-P202-P264-P270-P280-P301+P310+P330-P308+P313-P405-P501
Hazardous Substances Data
146464-95-1(Hazardous Substances Data)

Pralatrexate is a folate analogue metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

This study evaluated mechanistic differences of pralatrexate, methotrexate, and pemetrexed. Inhibition of dihydrofolate reductase (DHFR) was quantified using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts. Apparent K ( i ) values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more effective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts. Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity profile relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.

Biological Half-Life · 2 items

The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%).

The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance (CV) = 62-120%).

Metabolism/Metabolites · 2 items

While the liver has been shown to metabolize pralatrexate to some extent, pralatrexate is not significantly metabolized by any CYP450 isozymes or glucuronidases in vitro.

In vitro studies using human hepatocytes, liver microsomes and S9 fractions, and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases.

FDA Pharmacological Classification · 6 items

A8Q8I19Q20

PRALATREXATE

Established Pharmacologic Class [EPC] - Folate Analog Metabolic Inhibitor

Pralatrexate is a Folate Analog Metabolic Inhibitor.

PRALATREXATE

Folate Analog Metabolic Inhibitor [EPC]

Absorption, Distribution and Excretion · 6 items

With an intravenous formulation, pralatrexate has complete bioavailability. Pralatrexate demonstrates a dose-proportional and linear pharmacokinetics over a dose range of 30-325 mg/m2. Upon an intravenous push over 3 to 5 minutes of a starting dose of 30 mg/m2 racemic pralatrexate for dose 1 of cycle 1, Cmax and AUC0-∞ was estimated to be 5,815 ng/mL and 267,854 ng/mL.min respectively using a noncomparmental pharmacokinetics analysis.Both pralatrexate diastereomers demonstrates a multiphase decline in plasma concentration with a rapid initial fall followed by a slow terminal phase. The initial fall is thought to reflect the clearance of pralatrexate by renal and non-renal mechanism , while the slow terminal phase likely represents the return of pralatrexate from deep intracellular compartments, enterohepatic circulation, or after deglutamination.

Following a single dose of FOLOTYN 30 mg/m<sup>2</sup>, approximately 34% of the pralatrexate dose was excreted unchanged into urine. Following a radiolabeled pralatrexate dose, 39% (CV = 28%) of the dose was recovered in urine as unchanged pralatrexate and 34% (CV = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (CV = 95%) of the dose was exhaled over 24 hours.

The steady-state volume of distribution of pralatrexate S- and R-diastereomers is 105 L and 37 L, respectively.

The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer).

The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/sq m administered as an intravenous push over 3-5 minutes once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer).

Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with dose (dose range 30-325 mg/sq m, including pharmacokinetics data from high dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles, and no accumulation of pralatrexate was observed.

Uses & manufacturing

Uses · 2 items

MEDICATION

Pralatrexate is indicated for the treatment of ... relapsed or refractory peripheral T-cell lymphoma (PTCL). /Included in US product label/

Formulations/Preparations · 1 item

FOLOTYN (pralatrexate) is available in sterile, single-use vials containing pralatrexate at a concentration of 20 mg/mL in the following presentations: 20 mg of pralatrexate in 1 mL solution in a vial (20 mg / 1 mL); 40 mg of pralatrexate in 2 mL solution in a vial (40 mg / 2 mL).

Applications · 3 items

DescriptionPralatrexate, an injectable DHFR inhibitor, was launched for the treatment of patients with relapsed or refractory PTCL. PTCL is an aggressive form of non-Hodgkin’s lymphoma (NHL) characterized by the proliferation of abnormal T-lymphocytes that circulate in the peripheral bloodstream. The inhibition of the folate enzymes DHFR and thymidylate synthase is a well-validated method of cancer treatment. In vitro, pralatrexate is slightly less potent than MTX in inhibiting DHFR derived from murine leukemia L1210 cells (Ki = 18.2 pM vs. 5.75 pM) and human leukemia CCRF-CEM cells (Ki = 13.4 pM vs. 5.4 pM). However, it is transported into both types of cells with 10-fold higher efficiency than MTX, thereby providing a more potent inhibition of cell growth as compared with MTX. In vivo, intraperitonally administered pralatrexate at 60 mg/ kg twice weekly for three or four doses caused complete lymphoma regressions in 89, 56, and 30% of HT, RL, and SKI-DLBCL-1 xenografted mice, respectively, whereas a similar dosing of MTX at 40 mg/kg twice weekly did not produce complete regression. The posttreatment tumor diameter was also smaller in pralatrexate-treated animals.

DescriptionPralatrexate is a dihydrofolate reductase (DHFR) inhibitor (Ki = 13.4 pM) and antifolate. It inhibits growth of CCRF-CEM acute lymphocytic leukemia cells (IC50 = 0.04 μM), MDA-468, SK-BR-3, and ZR-75-1 breast cancer cells (IC50s = 0.11, 0.28, and 0.26 μM, respectively), and SK-LC8 and SK-LC16 non-small cell lung cancer cells (NSCLC; IC50s = 0.42 and 0.11 μM, respectively). In vivo, pralatrexate increases median survival from 21 to 40 days when administered in 4 doses of 15 mg/kg over 11 days in an H9 T cell lymphoma mouse xenograft model. Pralatrexate is transported into cells via the reduced folate carrier (RFC) and undergoes polyglutamation by folylpolyglutamate synthetase (FPGS) to a greater extent than methotrexate or pemetrexed . Formulations containing pralatrexate have been used in the treatment of relapsed or refractory peripheral T cell lymphoma.

UsesAn antifolate with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma.

Additional notes

DefinitionChEBI: A pteridine that is the N-4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl derivative of L-glutamic acid. Used for treatment of Peripheral T-Cell Lymphoma, an aggressive form of non-Hodgkins lymphoma.