pemetrexed Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definitionDrug idCAS RN
antineoplastics; thymidylate synthetase inhibitors 2073 137281-23-3

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • LY231514
  • pemetrexed diacid monohydrate
  • pemetrexed sodium
  • pemetrexed sodium hydrate
  • pemetrexed
  • pemetrexed disodium
  • alimta
  • pemetrexed disodium heptahydrate
Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), 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.
  • Molecular weight: 427.42
  • Formula: C20H21N5O6
  • CLOGP: -1.17
  • LIPINSKI: 2
  • HAC: 11
  • HDO: 6
  • TPSA: 186.97
  • ALOGS: -3.97
  • ROTB: 9

  • Status: OFP

  • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

None

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 3 Benet LZ, Broccatelli F, Oprea TI
S (Water solubility) 90 mg/mL Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 80 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 1.38 ┬ÁM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
Vd (Volume of distribution) 0.15 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 1.30 mL/min/kg Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma) 0.19 % Lombardo F, Berellini G, Obach RS
t_half (Half-life) 1.85 hours Lombardo F, Berellini G, Obach RS

Approvals:

DateAgencyCompanyOrphan
Sept. 20, 2004 EMA ELI LILLY NEDERLAND B.V.
Feb. 4, 2004 FDA LILLY

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Malignant neoplasm progression 532.95 40.63 150 2177 11978 2343780
Anaemia 336.04 40.63 138 2189 34654 2321104
Thrombocytopenia 333.71 40.63 117 2210 19014 2336744
Nausea 303.35 40.63 187 2140 112002 2243756
Neutropenia 301.53 40.63 112 2215 21436 2334322
Pancytopenia 298.94 40.63 95 2232 11357 2344401
Dehydration 283.26 40.63 108 2219 22187 2333571
Vomiting 268.62 40.63 148 2179 71454 2284304
Disease progression 221.06 40.63 84 2243 17011 2338747
Febrile neutropenia 218.08 40.63 74 2253 10808 2344950
Diarrhoea 196.25 40.63 128 2199 83436 2272322
Pneumonia 184.31 40.63 102 2225 49194 2306564
Dyspnoea 159.07 40.63 110 2217 78623 2277135
Platelet count decreased 156.11 40.63 64 2263 15749 2340009
Acute kidney injury 156.11 40.63 76 2251 28046 2327712
Mucosal inflammation 155.40 40.63 48 2279 5176 2350582
White blood cell count decreased 140.88 40.63 62 2265 18146 2337612
Decreased appetite 139.37 40.63 71 2256 28820 2326938
Off label use 134.93 40.63 97 2230 73501 2282257
Pleural effusion 131.57 40.63 52 2275 11616 2344142
Haemoglobin decreased 128.21 40.63 58 2269 18093 2337665
Renal failure 124.31 40.63 56 2271 17293 2338465
Pulmonary embolism 122.08 40.63 56 2271 18027 2337731
Pyrexia 119.91 40.63 80 2247 53628 2302130
Death 119.53 40.63 94 2233 81374 2274384
Neoplasm progression 118.41 40.63 38 2289 4630 2351128
Bone marrow failure 111.05 40.63 38 2289 5648 2350110
Sepsis 108.54 40.63 52 2275 18436 2337322
Hypokalaemia 108.01 40.63 44 2283 10610 2345148
General physical health deterioration 105.57 40.63 47 2280 14092 2341666
Rash 100.97 40.63 75 2252 59483 2296275
Asthenia 100.07 40.63 68 2259 46858 2308900
Neutrophil count decreased 94.52 40.63 35 2292 6532 2349226
Fatigue 91.37 40.63 82 2245 84791 2270967
Nephropathy toxic 91.30 40.63 23 2304 1165 2354593
Hepatocellular injury 86.62 40.63 29 2298 4026 2351732
Blood creatinine increased 84.99 40.63 37 2290 10496 2345262
Leukopenia 82.87 40.63 36 2291 10160 2345598
Respiratory failure 82.22 40.63 39 2288 13489 2342269
Non-small cell lung cancer 74.68 40.63 17 2310 556 2355202
Haemoptysis 74.44 40.63 25 2302 3502 2352256
Hyponatraemia 73.65 40.63 36 2291 13289 2342469
Constipation 70.26 40.63 41 2286 21588 2334170
Melanoderma 70.09 40.63 11 2316 40 2355718
Tubulointerstitial nephritis 66.53 40.63 21 2306 2417 2353341
Interstitial lung disease 58.32 40.63 26 2301 7786 2347972
Metastases to central nervous system 56.53 40.63 18 2309 2130 2353628
Chest pain 55.62 40.63 39 2288 28098 2327660
Renal impairment 54.94 40.63 27 2300 10065 2345693
Haematocrit decreased 54.78 40.63 21 2306 4297 2351461
Osteonecrosis of jaw 54.58 40.63 25 2302 7971 2347787
Pneumonitis 52.52 40.63 20 2307 4019 2351739
Malignant pleural effusion 52.45 40.63 12 2315 401 2355357
Haematotoxicity 48.91 40.63 14 2313 1153 2354605
Infection 47.73 40.63 30 2297 17999 2337759
Epistaxis 46.86 40.63 24 2303 9755 2346003
Lung adenocarcinoma 45.87 40.63 12 2315 705 2355053
Hypophagia 45.59 40.63 18 2309 3982 2351776
Cellulitis 45.30 40.63 23 2304 9178 2346580
Oedema peripheral 44.76 40.63 32 2295 23731 2332027
Headache 43.68 40.63 54 2273 80125 2275633
Deep vein thrombosis 43.22 40.63 25 2302 12907 2342851
Mental status changes 43.00 40.63 19 2308 5563 2350195
Blood albumin decreased 42.97 40.63 14 2313 1781 2353977
Radiation pneumonitis 42.78 40.63 9 2318 202 2355556
Pericardial effusion 42.07 40.63 17 2310 3992 2351766
Hyperkalaemia 42.01 40.63 19 2308 5874 2349884
Aspartate aminotransferase increased 41.14 40.63 24 2303 12588 2343170

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Malignant neoplasm progression 731.13 49.57 254 3791 13904 1728832
Pancytopenia 637.03 49.57 217 3828 11140 1731596
Anaemia 624.31 49.57 277 3768 29180 1713556
Neutropenia 571.46 49.57 227 3818 18033 1724703
Thrombocytopenia 528.08 49.57 224 3821 21025 1721711
General physical health deterioration 437.20 49.57 171 3874 12947 1729789
Febrile neutropenia 431.82 49.57 162 3883 10938 1731798
Dehydration 404.42 49.57 176 3869 17482 1725254
Interstitial lung disease 400.72 49.57 148 3897 9548 1733188
Pneumonia 399.88 49.57 238 3807 45944 1696792
Mucosal inflammation 356.38 49.57 110 3935 4059 1738677
Nausea 354.60 49.57 229 3816 50967 1691769
Diarrhoea 341.57 49.57 228 3817 53624 1689112
Dyspnoea 341.24 49.57 225 3820 51834 1690902
Vomiting 334.93 49.57 199 3846 38116 1704620
Decreased appetite 306.81 49.57 160 3885 23711 1719025
Pyrexia 299.85 49.57 199 3846 46201 1696535
Pleural effusion 274.24 49.57 117 3928 10993 1731743
Platelet count decreased 265.56 49.57 129 3916 16394 1726342
Sepsis 263.02 49.57 135 3910 19303 1723433
Bone marrow failure 261.75 49.57 92 3953 5108 1737628
White blood cell count decreased 245.88 49.57 114 3931 13035 1729701
Acute kidney injury 235.14 49.57 154 3891 34790 1707946
Asthenia 226.44 49.57 150 3895 34520 1708216
Leukopenia 221.36 49.57 93 3952 8387 1734349
Renal failure 192.51 49.57 111 3934 19906 1722830
Neutrophil count decreased 179.96 49.57 73 3972 6008 1736728
Pulmonary embolism 177.13 49.57 91 3954 12968 1729768
Septic shock 169.26 49.57 76 3969 8033 1734703
Respiratory failure 168.13 49.57 91 3954 14414 1728322
Haemoglobin decreased 167.37 49.57 96 3949 17018 1725718
Rash 164.21 49.57 129 3916 38564 1704172
Fatigue 157.08 49.57 141 3904 50640 1692096
Disease progression 137.82 49.57 85 3960 17178 1725558
Death 129.43 49.57 164 3881 87279 1655457
Neoplasm progression 120.37 49.57 46 3999 3221 1739515
Off label use 116.80 49.57 106 3939 38465 1704271
Haemoptysis 115.52 49.57 50 3995 4826 1737910
Epistaxis 112.80 49.57 58 3987 8248 1734488
Pneumonitis 112.30 49.57 46 3999 3869 1738867
Blood creatinine increased 112.06 49.57 69 3976 13877 1728859
Hypotension 110.94 49.57 92 3953 29562 1713174
Atrial fibrillation 106.98 49.57 69 3976 15042 1727694
Non-small cell lung cancer 103.49 49.57 28 4017 634 1742102
Constipation 97.64 49.57 65 3980 14935 1727801
Lung disorder 97.30 49.57 45 4000 5074 1737662
Febrile bone marrow aplasia 95.67 49.57 28 4017 850 1741886
Disseminated intravascular coagulation 95.32 49.57 40 4005 3574 1739162
Stomatitis 94.97 49.57 45 4000 5359 1737377
Colitis 92.93 49.57 41 4004 4139 1738597
Enteritis 88.41 49.57 27 4018 951 1741785
Peritonitis 88.25 49.57 35 4010 2704 1740032
Oedema peripheral 83.79 49.57 60 3985 15490 1727246
Blood sodium decreased 83.26 49.57 32 4013 2272 1740464
Neutropenic sepsis 81.06 49.57 28 4017 1464 1741272
Hypophagia 79.99 49.57 35 4010 3462 1739274
Renal impairment 79.22 49.57 53 3992 12261 1730475
C-reactive protein increased 73.84 49.57 39 4006 5846 1736890
Infection 69.57 49.57 49 3996 12311 1730425
Aphthous ulcer 68.87 49.57 21 4024 735 1742001
Hyponatraemia 68.34 49.57 43 4002 8957 1733779
Hyperkalaemia 67.83 49.57 42 4003 8505 1734231
Lymphocyte count decreased 67.02 49.57 27 4018 2171 1740565
Oesophagitis 66.40 49.57 25 4020 1676 1741060
Lung adenocarcinoma 65.59 49.57 20 4025 700 1742036
Large intestine perforation 63.50 49.57 22 4023 1160 1741576
Purpura 61.81 49.57 24 4021 1750 1740986
Haematocrit decreased 61.31 49.57 31 4014 4242 1738494
Confusional state 61.30 49.57 57 3988 21221 1721515
Weight decreased 59.93 49.57 58 3987 22695 1720041
Deep vein thrombosis 59.72 49.57 41 4004 9879 1732857
Abdominal pain 58.90 49.57 56 3989 21434 1721302
Dysphagia 58.81 49.57 41 4004 10127 1732609
Hiccups 58.71 49.57 22 4023 1455 1741281
Malaise 57.42 49.57 64 3981 29501 1713235
Performance status decreased 56.63 49.57 18 4027 724 1742012
Pneumonia aspiration 55.22 49.57 31 4014 5235 1737501
Pneumothorax 55.13 49.57 25 4020 2687 1740049
Syncope 54.99 49.57 45 4000 14124 1728612
Pericardial effusion 52.78 49.57 26 4019 3364 1739372
Lung cancer metastatic 52.69 49.57 16 4029 552 1742184
Neoplasm malignant 52.28 49.57 28 4017 4311 1738425
Pain 52.25 49.57 58 3987 26599 1716137
Cardiac failure 50.95 49.57 41 4004 12561 1730175
Erythema 50.77 49.57 43 4002 14145 1728591
Lung infiltration 50.63 49.57 22 4023 2137 1740599
Multiple organ dysfunction syndrome 50.50 49.57 36 4009 9206 1733530

Pharmacologic Action:

SourceCodeDescription
ATC L01BA04 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
ANTIMETABOLITES
Folic acid analogues
FDA EPC N0000175584 Folate Analog Metabolic Inhibitor
FDA MoA N0000000111 Folic Acid Metabolism Inhibitors
MeSH PA D000970 Antineoplastic Agents
MeSH PA D004791 Enzyme Inhibitors
MeSH PA D005493 Folic Acid Antagonists
MeSH PA D019384 Nucleic Acid Synthesis Inhibitors
CHEBI has role CHEBI:35610 antineoplastic agent

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Non-small cell lung cancer indication 254637007 DOID:3908
Malignant mesothelioma of pleura indication 254645002 DOID:7474
Kidney disease contraindication 90708001 DOID:557
Impaired renal function disorder contraindication 197663003
Anemia contraindication 271737000 DOID:2355
Pregnancy, function contraindication 289908002
Thrombocytopenic disorder contraindication 302215000 DOID:1588
Neutropenic disorder contraindication 303011007 DOID:1227
Breastfeeding (mother) contraindication 413712001

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 3.34 acidic
pKa2 5.15 acidic
pKa3 9.45 acidic
pKa4 13.09 acidic
pKa5 3.95 Basic

Orange Book patent data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
EQ 100MG BASE/VIAL ALIMTA LILLY N021462 Sept. 7, 2007 RX POWDER INTRAVENOUS 7772209 Nov. 24, 2021 USE OF PEMETREXED WITH PRIOR AND/OR REPEATED VITAMIN B12 AND FOLIC ACID ADMINISTRATION
EQ 500MG BASE/VIAL ALIMTA LILLY N021462 Feb. 4, 2004 RX POWDER INTRAVENOUS 7772209 Nov. 24, 2021 USE OF PEMETREXED WITH PRIOR AND/OR REPEATED VITAMIN B12 AND FOLIC ACID ADMINISTRATION
500MG/20ML (25MG/ML) PEMFEXY EAGLE PHARMS N209472 Feb. 8, 2020 RX SOLUTION INTRAVENOUS 7772209 May 24, 2022 USE OF PEMETREXED WITH PRIOR AND/OR REPEATED VITAMIN B12 AND FOLIC ACID ADMINISTRATION IN PATIENTS WITH MESOTHELIOMA
500MG/20ML (25MG/ML) PEMFEXY EAGLE PHARMS N209472 Feb. 8, 2020 RX SOLUTION INTRAVENOUS 7772209 May 24, 2022 USE OF PEMETREXED WITH PRIOR AND/OR REPEATED VITAMIN B12 AND FOLIC ACID ADMINISTRATION IN PATIENTS WITH NON-SQUAMOUS NON-SMALL CELL LUNG CANCER

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Dihydrofolate reductase Enzyme INHIBITOR IC50 5.18 WOMBAT-PK CHEMBL
Trifunctional purine biosynthetic protein adenosine-3 Enzyme INHIBITOR Ki 6.42 CHEMBL DRUG LABEL
Thymidylate synthase Enzyme INHIBITOR IC50 6.47 WOMBAT-PK CHEMBL
Serine hydroxymethyltransferase, cytosolic Enzyme Kd 4.77 CHEMBL
Proton-coupled folate transporter Transporter Ki 7.03 CHEMBL
Folate transporter 1 Unclassified IC50 6.86 CHEMBL
Folate receptor beta Membrane receptor IC50 7.22 CHEMBL
Folate receptor alpha Membrane receptor IC50 7.38 CHEMBL
Folylpolyglutamate synthase, mitochondrial Enzyme WOMBAT-PK
Bifunctional dihydrofolate reductase-thymidylate synthase Enzyme IC50 6.37 CHEMBL
Thymidylate synthase Enzyme IC50 5.96 CHEMBL
Thymidylate synthase Enzyme Ki 6.26 CHEMBL
Thymidylate synthase Enzyme IC50 4.70 CHEMBL
Dihydrofolate reductase Unclassified IC50 5.64 CHEMBL
Thymidylate synthase Enzyme Ki 6.47 CHEMBL
Dihydrofolate reductase Enzyme Ki 6.25 CHEMBL
Thymidylate synthase (EC 2.1.1.45) (TS) (TSase) Enzyme IC50 4.12 CHEMBL
Trifunctional purine biosynthetic protein adenosine-3 Unclassified INHIBITOR Ki 5.03 IUPHAR
Dihydrofolate reductase Enzyme IC50 5.64 CHEMBL

External reference:

IDSource
D000068437 MESH_DESCRIPTOR_UI
4021417 VUID
N0000148831 NUI
C0210657 UMLSCUI
D03828 KEGG_DRUG
04Q9AIZ7NO UNII
7675 INN_ID
150399-23-8 SECONDARY_CAS_RN
411089001 SNOMEDCT_US
4021417 VANDF
68446 RXNORM
d05047 MMSL
17856 MMSL
409159000 SNOMEDCT_US
008494 NDDF
CHEMBL225072 ChEMBL_ID
DB00642 DRUGBANK_ID
4DW PDB_CHEM_ID
LYA PDB_CHEM_ID
CHEBI:63616 CHEBI
CHEMBL1201258 ChEMBL_ID
CHEMBL2360464 ChEMBL_ID
135410875 PUBCHEM_CID
6837 IUPHAR_LIGAND_ID

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Alimta HUMAN PRESCRIPTION DRUG LABEL 1 0002-7623 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 500 mg INTRAVENOUS NDA 19 sections
Alimta HUMAN PRESCRIPTION DRUG LABEL 1 0002-7640 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 100 mg INTRAVENOUS NDA 19 sections