Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Structure

Similar Structures

Synonyms

(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
10-Propargyl-10-deazaaminopterin
N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
PDX
Pralatrexate
Pralatrexato
Pralatrexatum

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Folotyn	Injection	20 mg/1mL	Intravenous	Allos Therapeutics	2009-09-24	Not applicable

Categories

UNII

A8Q8I19Q20

CAS number

146464-95-1

Weight

Average: 477.4726
Monoisotopic: 477.176066881

Chemical Formula

C₂₃H₂₃N₇O₅

InChI Key

OGSBUKJUDHAQEA-WMCAAGNKSA-N

InChI

InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1

IUPAC Name

(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid

SMILES

NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1

Pharmacology

Indication

Treatment of relapsed or refractory peripheral T-cell lymphoma.

Associated Conditions

Pharmacodynamics

Pralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9

Mechanism of action

The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell.
Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

Target	Actions	Organism
ADihydrofolate reductase	inhibitor	Humans
AThymidylate synthase	inhibitor	Humans

Absorption

Pralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%

Volume of distribution

Vss, R-pralatrexate = 37 L Vss, S-pralatrexate = 105 L

Protein binding

67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.

Metabolism

No involvement of CYP450 enzyme system or glucuronidases.

Route of elimination

35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.

Half life

12-18 hours

Clearance

R- pralatrexate = 191 mL/min S- pralatrexate = 417 mL/min Mean clearance of both enantiomers is 220 mL/min.

Toxicity

Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
(6R)-Folinic acid	The therapeutic efficacy of Pralatrexate can be decreased when used in combination with (6R)-Folinic acid.
(6S)-5,6,7,8-tetrahydrofolate	The therapeutic efficacy of Pralatrexate can be decreased when used in combination with (6S)-5,6,7,8-tetrahydrofolate.
2-Methoxyethanol	The risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Pralatrexate.
9-(N-methyl-L-isoleucine)-cyclosporin A	The risk or severity of adverse effects can be increased when Pralatrexate is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
Abacavir	Abacavir may decrease the excretion rate of Pralatrexate which could result in a higher serum level.
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Pralatrexate.
Abetimus	The risk or severity of adverse effects can be increased when Abetimus is combined with Pralatrexate.
Acarbose	Acarbose may decrease the excretion rate of Pralatrexate which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Pralatrexate which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Pralatrexate which could result in a higher serum level.

Food Interactions

Not Available

References

General References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]
Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. [PubMed:23032692]

External Links

KEGG Drug: D05589
PubChem Compound: 148121
PubChem Substance: 175427094
ChemSpider: 130578
ChEBI: 71223
ChEMBL: CHEMBL1201746
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Pralatrexate

ATC Codes

L01BA05 — Pralatrexate

FDA label

Download (266 KB)

MSDS

Download (479 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Treatment	Advanced Cancers / Tumors, Solid	1
1	Completed	Treatment	Cutaneous T-Cell Lymphoma (CTCL)	1
1	Completed	Treatment	Cutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Primary Cutaneous Anaplastic Large Cell Lymphoma / Sezary Syndrome	1
1	Completed	Treatment	Multiple Myeloma (MM)	1
1	Completed	Treatment	Unspecified Adult Solid Tumor, Protocol Specific	2
1	Recruiting	Other	CTCL / PTCL	1
1	Recruiting	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
1	Withdrawn	Prevention	Lung Cancer Non-Small Cell Cancer (NSCLC)	1
1	Withdrawn	Prevention	Non Hodgkin Lymphoma (NHL)	1
1, 2	Completed	Treatment	Cancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm	1
1, 2	Completed	Treatment	Lymphoma, B-Cell / Lymphoma, Hodgkins / Peripheral T-Cell Lymphoma (PTCL) / Relapsed or Refractory Lymphoproliferative Malignancies / Waldenström's Macroglobulinemia (WM)	1
1, 2	Completed	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
1, 2	Recruiting	Treatment	Lymphoid Malignancies / Lymphoma, Hodgkins / Malignant Lymphomas / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)	1
1, 2	Recruiting	Treatment	Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma / Recurrent Mycosis Fungoides / Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma / Refractory, advanced Mycosis fungoides	1
1, 2	Recruiting	Treatment	T-Cell Lymphomas	1
2	Completed	Treatment	Adenocarcinoma of the Esophagus / Adenocarcinomas of the Gastroesophageal Junction / Recurrent Esophageal Cancer / Squamous Cell Carcinoma of the Esophagus / Stage IV Esophageal Cancer	1
2	Completed	Treatment	Adenocarcinomas of the Gastroesophageal Junction / Advanced Gastric Cancer / Esophageal Undifferentiated Carcinoma / Gastric Adenocarcinoma / Gastric Squamous Cell Carcinoma / Recurrent Esophageal Adenocarcinoma / Recurrent Esophageal Squamous Cell Carcinoma / Recurrent Gastric Carcinoma / Stage IIIB Esophageal Adenocarcinoma / Stage IIIB Esophageal Squamous Cell Carcinoma / Stage IIIB Gastric Cancer / Stage IIIC Esophageal Adenocarcinoma / Stage IIIC Esophageal Squamous Cell Carcinoma / Stage IIIC Gastric Cancer / Stage IV Esophageal Adenocarcinoma / Stage IV Esophageal Squamous Cell Carcinoma / Undifferentiated Gastric Carcinoma	1
2	Completed	Treatment	Adult T-cell lymphomas/leukaemias	1
2	Completed	Treatment	Anaplastic Large Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Hepatosplenic T-Cell Lymphoma / Peripheral T-Cell Lymphoma (PTCL)	1
2	Completed	Treatment	Bladder Cancers / Neoplasm, Bladder / Transitional Cell Carcinoma	1
2	Completed	Treatment	Cancer of the Breast / Cancer, Breast / Human Mammary Carcinoma / Neoplasms, Breast / Tumors, Breast	1
2	Completed	Treatment	Lung Cancer Non-Small Cell Cancer (NSCLC)	1
2	Completed	Treatment	Lung Cancers	1
2	Completed	Treatment	Lymphoma, B-Cell	1
2	Completed	Treatment	Malignant Lymphomas	1
2	Completed	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
2	Recruiting	Prevention	Refractory Peripheral T-cell Lymphoma Unspecified / Relapsed Peripheral T-Cell Lymphoma	1
3	Active Not Recruiting	Treatment	Recurrent Cutaneous T-cell lymphoma / Refractory Peripheral T-cell Lymphoma Unspecified	1
3	Completed	Treatment	Refractory Peripheral T-cell Lymphoma Unspecified / Relapsed Peripheral T-Cell Lymphoma	1
3	Terminated	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
3	Withdrawn	Other	Lymphoma, T-Cell, Peripheral	1
4	Recruiting	Treatment	Peripheral T Cell Lymphoma (PTCL) / Progression, Disease	1
Not Available	Completed	Not Available	Relapsed or Refractory Peripheral T-cell Lymphoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Injection	Intravenous	20 mg/1mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US6028071	No	2000-02-22	2022-07-16
US7622470	No	2009-11-24	2025-05-31
US8299078	No	2012-10-30	2025-05-31

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0178 mg/mL	ALOGPS
logP	0.1	ALOGPS
logP	0.33	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	3.44	ChemAxon
pKa (Strongest Basic)	2.86	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	11	ChemAxon
Hydrogen Donor Count	5	ChemAxon
Polar Surface Area	207.3 Å²	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	126.82 m³·mol^-1	ChemAxon
Polarizability	47.31 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	-	0.6139
Blood Brain Barrier	+	0.5561
Caco-2 permeable	-	0.7518
P-glycoprotein substrate	Substrate	0.5845
P-glycoprotein inhibitor I	Non-inhibitor	0.9224
P-glycoprotein inhibitor II	Non-inhibitor	0.9921
Renal organic cation transporter	Non-inhibitor	0.938
CYP450 2C9 substrate	Non-substrate	0.8589
CYP450 2D6 substrate	Non-substrate	0.8269
CYP450 3A4 substrate	Non-substrate	0.6396
CYP450 1A2 substrate	Non-inhibitor	0.8654
CYP450 2C9 inhibitor	Non-inhibitor	0.8965
CYP450 2D6 inhibitor	Non-inhibitor	0.9073
CYP450 2C19 inhibitor	Non-inhibitor	0.9178
CYP450 3A4 inhibitor	Non-inhibitor	0.6523
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.934
Ames test	Non AMES toxic	0.8727
Carcinogenicity	Non-carcinogens	0.9543
Biodegradation	Not ready biodegradable	0.9493
Rat acute toxicity	2.6263 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9803
hERG inhibition (predictor II)	Non-inhibitor	0.8735

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-004i-1513900000-5596beb52832aa3566cc

Taxonomy

Description: This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid 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: Glutamic acid and derivatives
Alternative Parents: N-acyl-alpha amino acids / Hippuric acids / Pteridines and derivatives / Aromatic monoterpenoids / Bicyclic monoterpenoids / Benzoyl derivatives / Aminopyrimidines and derivatives / Pyrazines / Imidolactams / Dicarboxylic acids and derivatives
show 11 more
Substituents: Glutamic acid or derivatives / Hippuric acid / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Hippuric acid or derivatives / P-cymene / Aromatic monoterpenoid / Monoterpenoid / Bicyclic monoterpenoid / Pteridine
show 29 more
Molecular Framework: Aromatic heteropolycyclic compounds
External Descriptors: terminal acetylenic compound, N-acyl-L-glutamic acid, pteridines (CHEBI:71223)

Targets

Details1. Dihydrofolate reductase

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Nadph binding
Specific Function: Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA pre...
Gene Name: DHFR
Uniprot ID: P00374
Uniprot Name: Dihydrofolate reductase
Molecular Weight: 21452.61 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]

Details2. Thymidylate synthase

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Thymidylate synthase activity
Specific Function: Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name: TYMS
Uniprot ID: P04818
Uniprot Name: Thymidylate synthase
Molecular Weight: 35715.65 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]

Enzymes

Details1. Folylpolyglutamate synthase, mitochondrial

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Tetrahydrofolylpolyglutamate synthase activity
Specific Function: Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrate...
Gene Name: FPGS
Uniprot ID: Q05932
Uniprot Name: Folylpolyglutamate synthase, mitochondrial
Molecular Weight: 64608.53 Da

References

Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]

Transporters

Details1. Folate transporter 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Reduced folate carrier activity
Specific Function: Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely th...
Gene Name: SLC19A1
Uniprot ID: P41440
Uniprot Name: Folate transporter 1
Molecular Weight: 64867.62 Da

References

Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]

Drug created on September 14, 2010 10:21 / Updated on April 10, 2019 13:51

Pralatrexate

Identification

Structure for Pralatrexate (DB06813)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References

Enzymes

References

Transporters

References