U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C20H21N5O6
Molecular Weight 427.4114
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEMETREXED

SMILES

c1cc(ccc1CCc2c[nH]c3c2c(nc(=N)[nH]3)O)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)O

InChI

InChIKey=WBXPDJSOTKVWSJ-ZDUSSCGKSA-N
InChI=1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1

HIDE SMILES / InChI

Description
Curator's Comment:: https://www.ncbi.nlm.nih.gov/pubmed/17308042

Pemetrexed, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and and to a lesser extent aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

CNS Activity

Curator's Comment:: Human data not available, but is known that pemetrexed-based treatments controls of brain metastases in the treatment of non-small-cell lung cancer https://www.ncbi.nlm.nih.gov/pubmed/21831719

Originator

Curator's Comment:: # Eli Lilly

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
109 nM [Ki]
7 nM [Ki]
9300 nM [Ki]
3580 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ALIMTA

Approved Use

ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3)

Launch Date

1092873600000
Primary
ALIMTA

Approved Use

ALIMTA® is a folate analog metabolic inhibitor indicated for: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Initial treatment in combination with cisplatin. (1.1) Maintenance treatment of patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.2) After prior chemotherapy as a single-agent. (1.3) Mesothelioma: in combination with cisplatin. (1.4) Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. (1.5) 1.1 Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.3 Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA is indicated as a single-agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 1.4 Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies (14.1, 14.2, 14.3)

Launch Date

1092873600000
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
137 μg/mL
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
164 μg × h/mL
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3.71 h
500 mg/m² other, intravenous
dose: 500 mg/m²
route of administration: Intravenous
experiment type: OTHER
co-administered:
PEMETREXED blood
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
19%
PEMETREXED plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
DLT: Lymphopenia...
Other AEs: Neutropenia, Fatigue...
Dose limiting toxicities:
Lymphopenia (grade 4, 2 patients)
Other AEs:
Neutropenia (grade 3-4)
Fatigue (grade 3-4)
Sources:
900 mg/m2 1 times / 2 weeks multiple, intravenous
MTD
Dose: 900 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 900 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Disc. AE: Transaminases increased...
AEs leading to
discontinuation/dose reduction:
Transaminases increased (1 patient)
Sources:
600 mg/m2 1 times / 2 weeks multiple, intravenous
Dose: 600 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 600 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
DLT: Neutropenia...
Dose limiting toxicities:
Neutropenia (grade 4, 1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
Fatigue grade 3-4
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Neutropenia grade 3-4
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Lymphopenia grade 4, 2 patients
DLT
1200 mg/m2 1 times / 2 weeks multiple, intravenous
Highest studied dose
Dose: 1200 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 1200 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Transaminases increased 1 patient
Disc. AE
900 mg/m2 1 times / 2 weeks multiple, intravenous
MTD
Dose: 900 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 900 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Neutropenia grade 4, 1 patient
DLT, Disc. AE
600 mg/m2 1 times / 2 weeks multiple, intravenous
Dose: 600 mg/m2, 1 times / 2 weeks
Route: intravenous
Route: multiple
Dose: 600 mg/m2, 1 times / 2 weeks
Sources:
unhealthy, 63.7 years (range: 47–77 years)
Health Status: unhealthy
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Sources:
Overview

Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer





Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
yes
yes
weak (co-administration study)
Comment: coadministration with ibuprofen decreased the clearance of pemetrexed and increased its expsoure (AUC) by ~ 20%
Page: 17
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.
2001
A new route to 7-substituted derivatives of n-[4-(2-[2-amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimidin-5-yl]ethyl)benzoyl]-L-glutamic acid [ALIMTA (LY231514, MTA)].
2001 Jun 1
Pemetrexed (Alimta): a novel multitargeted antifolate agent.
2003 Apr
Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents.
2003 Feb 13
Accumulation of 5-phosphoribosyl-1-pyrophosphate in human CCRF-CEM leukaemia cells treated with antifolates.
2004 Mar
Biochemical pharmacology of pemetrexed.
2004 Nov
Pemetrexed: a multitargeted antifolate.
2005 Sep
Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications.
2007 Feb
Pemetrexed: a review of its use in the management of advanced non-squamous non-small cell lung cancer.
2009 Nov 12
Patents

Sample Use Guides

Combination ALIMTA (pemetrexed disodium) use in Non-Small Cell Lung Cancer and Mesothelioma: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 30 minutes after ALIMTA administration.
Route of Administration: Intravenous
pemetrexed has a potent cytotoxic effect against human peripheral blood lymphocytes at concentrations 25, 50, 75 and 100 μg/mL (concentrations roughly 2,25–9 times less than the maximum plasma level (225 μg/mL) achieved in patients receiving this drug) based on the top concentration (100 μg/mL)
Name Type Language
PEMETREXED
EMA EPAR   HSDB   INN   MI   VANDF   WHO-DD  
INN  
Official Name English
PEMETREXED [INN]
Common Name English
PEMFEXY
Brand Name English
N-(P-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-1H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-L-GLUTAMATE
Systematic Name English
PEMETREXED [HSDB]
Common Name English
L-GLUTAMIC ACID, N-(4-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-3H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-
Systematic Name English
N-(4-(2-(2-AMINO-4,7-DIHYDRO-4-OXO-1H-PYRROLO(2,3-D)PYRIMIDIN-5-YL)ETHYL)BENZOYL)-L-GLUTAMIC ACID
Systematic Name English
PEMETREXED [WHO-DD]
Common Name English
LY-231514
Code English
PEMETREXED [EMA EPAR]
Common Name English
LY231514
Code English
PEMETREXED [MI]
Common Name English
PEMETREXED [VANDF]
Common Name English
NSC-698037
Code English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS PEMETREXED LILLY (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
EMA ASSESSMENT REPORTS ALIMTA (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
WHO-ATC L01BA04
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
NDF-RT N0000000111
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
LIVERTOX 749
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
NCI_THESAURUS C2021
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
EMA ASSESSMENT REPORTS PEMETREXED HOSPIRA (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
NCI_THESAURUS C511
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
NDF-RT N0000175584
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
WHO-VATC QL01BA04
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
EMA ASSESSMENT REPORTS PEMETREXED MEDAC (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
Code System Code Type Description
MERCK INDEX
M8456
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY Merck Index
MESH
C085586
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
DRUG CENTRAL
2073
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
PUBCHEM
135410875
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
FDA UNII
04Q9AIZ7NO
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
LACTMED
Pemetrexed
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
INN
7675
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
RXCUI
68446
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY RxNorm
IUPHAR
6837
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
WIKIPEDIA
PEMETREXED
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
CAS
137281-23-3
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
ChEMBL
CHEMBL1201258
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
EPA CompTox
137281-23-3
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
EVMPD
SUB09655MIG
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
DRUG BANK
DB00642
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
NCI_THESAURUS
C61614
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY
HSDB
7316
Created by admin on Sat Jun 26 01:05:53 UTC 2021 , Edited by admin on Sat Jun 26 01:05:53 UTC 2021
PRIMARY