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Details

Stereochemistry ABSOLUTE
Molecular Formula C20H21N5O6.H2O
Molecular Weight 445.4259
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEMETREXED MONOHYDRATE

SMILES

O.NC1=NC2=C(C(CCC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CN2)C(=O)N1

InChI

InChIKey=NBNBOZLBWLNZHB-ZOWNYOTGSA-N
InChI=1S/C20H21N5O6.H2O/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);1H2/t13-;/m0./s1

HIDE SMILES / InChI

Molecular Formula C20H21N5O6
Molecular Weight 427.4106
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/9762351 https://www.ncbi.nlm.nih.gov/pubmed/17308042

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. 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: Known to be CNS penetrant in rodents https://www.ncbi.nlm.nih.gov/pubmed/15987831 https://www.ncbi.nlm.nih.gov/pubmed/23297298 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
109.0 nM [Ki]
7.0 nM [Ki]
9300.0 nM [Ki]
3580.0 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

1.09287362E12
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

1.09287362E12
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)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
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)
n = 4
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 4
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)
n = 6
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 6
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)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
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)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
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)
n = 7
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 7
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)
n = 4
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 4
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)
n = 6
Health Status: unhealthy
Condition: Recurrent or Progressive Central Nervous System Lymphoma
Age Group: 63.7 years (range: 47–77 years)
Sex: M+F
Population Size: 6
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: 17.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors.
2001
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
Pemetrexed: a multitargeted antifolate.
2005 Sep
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. Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.
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)
Substance Class Chemical
Created
by admin
on Thu Jul 06 14:05:18 UTC 2023
Edited
by admin
on Thu Jul 06 14:05:18 UTC 2023
Record UNII
236Y2F7D9J
Record Status Validated (UNII)
Record Version
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Name Type Language
PEMETREXED MONOHYDRATE
WHO-DD  
Common Name English
ARMISARTE
Brand Name English
PEMETREXED DIACID MONOHYDRATE
Common Name English
Pemetrexed monohydrate [WHO-DD]
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)-, MONOHYDRATE
Systematic Name English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS ARMISARTE (AUTHORIZED: CARCINOMA, NON-SMALL-CELL LUNG, MESOTHELIOMA)
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
Code System Code Type Description
DAILYMED
236Y2F7D9J
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
RXCUI
2590669
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
FDA UNII
236Y2F7D9J
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
PUBCHEM
135565166
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
SMS_ID
100000160644
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
DRUG BANK
DBSALT002627
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
EVMPD
SUB172905
Created by admin on Thu Jul 06 14:05:18 UTC 2023 , Edited by admin on Thu Jul 06 14:05:18 UTC 2023
PRIMARY
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PARENT -> SALT/SOLVATE
ANHYDROUS->SOLVATE
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ACTIVE MOIETY