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 ยตM/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 544.88 18.63 297 13197 64629 46607939
Disease progression 234.63 18.63 201 13293 91099 46581469
Pancytopenia 157.47 18.63 156 13338 84902 46587666
Anaemia 139.66 18.63 258 13236 255521 46417047
Neutropenia 134.16 18.63 185 13309 143019 46529549
Bone marrow failure 121.07 18.63 86 13408 29583 46642985
Thrombocytopenia 111.75 18.63 159 13335 126422 46546146
Neoplasm progression 103.48 18.63 75 13419 26608 46645960
Metastases to central nervous system 101.21 18.63 54 13440 11167 46661401
Febrile neutropenia 94.18 18.63 126 13368 94501 46578067
Drug resistance 91.51 18.63 59 13435 17309 46655259
Non-small cell lung cancer 68.92 18.63 28 13466 3116 46669452
Pneumonitis 67.62 18.63 60 13434 28360 46644208
Dehydration 67.60 18.63 145 13349 159395 46513173
Mucosal inflammation 67.44 18.63 69 13425 38907 46633661
Lung adenocarcinoma 67.44 18.63 30 13464 4174 46668394
Nephropathy toxic 64.77 18.63 35 13459 7419 46665149
Lung neoplasm malignant 56.56 18.63 42 13452 15447 46657121
Acquired gene mutation 56.16 18.63 16 13478 600 46671968
Hepatocellular injury 56.10 18.63 55 13439 29467 46643101
Tubulointerstitial nephritis 56.02 18.63 41 13453 14747 46657821
Haematotoxicity 55.94 18.63 31 13463 6902 46665666
Metastases to meninges 55.80 18.63 21 13473 1906 46670662
Rheumatoid arthritis 54.17 18.63 4 13490 240211 46432357
Malignant pleural effusion 50.84 18.63 21 13473 2437 46670131
Death 49.70 18.63 210 13284 335338 46337230
Therapy partial responder 49.28 18.63 25 13469 4657 46667911
Melanoderma 48.77 18.63 11 13483 156 46672412
Neutrophil count decreased 48.08 18.63 61 13433 43365 46629203
Non-small cell lung cancer metastatic 47.00 18.63 14 13480 615 46671953
Metastases to adrenals 45.75 18.63 14 13480 675 46671893
Arthralgia 44.66 18.63 25 13469 364578 46307990
Pleural effusion 44.17 18.63 83 13411 82869 46589699
Drug hypersensitivity 43.09 18.63 9 13485 243816 46428752
Posterior reversible encephalopathy syndrome 42.18 18.63 35 13459 15106 46657462
Lung adenocarcinoma stage IV 41.90 18.63 10 13484 184 46672384
Subacute cutaneous lupus erythematosus 41.78 18.63 17 13477 1898 46670670
Haemoptysis 41.06 18.63 44 13450 26145 46646423
Renal tubular disorder 40.85 18.63 18 13476 2447 46670121
Fall 39.66 18.63 23 13471 329074 46343494
Vomiting 39.35 18.63 244 13250 452550 46220018
Nausea 38.85 18.63 334 13160 687120 45985448
Product dose omission issue 37.42 18.63 3 13491 168517 46504051
Renal failure 36.80 18.63 93 13401 113501 46559067
Off label use 36.36 18.63 210 13284 379631 46292937
Drug ineffective 36.33 18.63 90 13404 677748 45994820
Performance status decreased 36.17 18.63 18 13476 3219 46669349
White blood cell count decreased 35.43 18.63 91 13403 112140 46560428
Pulmonary embolism 35.27 18.63 89 13405 108496 46564072
Immune-mediated pancreatitis 35.14 18.63 7 13487 52 46672516
Secondary hypertension 34.99 18.63 8 13486 121 46672447
Hypertransaminasaemia 34.90 18.63 18 13476 3470 46669098
Lung cancer metastatic 34.49 18.63 16 13478 2452 46670116
Renal tubular necrosis 34.49 18.63 27 13467 10732 46661836
Pain 34.46 18.63 53 13441 476895 46195673
Osteonecrosis of jaw 34.45 18.63 46 13448 34356 46638212
Joint swelling 34.13 18.63 4 13490 166069 46506499
General physical health deterioration 31.64 18.63 89 13405 115680 46556888
Lymphangiosis carcinomatosa 31.23 18.63 12 13482 1152 46671416
Gamma-glutamyltransferase increased 31.11 18.63 42 13452 31698 46640870
Multiple-drug resistance 30.86 18.63 15 13479 2550 46670018
Decreased appetite 30.71 18.63 124 13370 193712 46478856
Blood creatinine increased 30.64 18.63 68 13426 76335 46596233
Myocarditis 30.54 18.63 22 13472 7717 46664851
Radiation pneumonitis 30.34 18.63 12 13482 1245 46671323
Metastases to bone 30.32 18.63 31 13463 17445 46655123
Non-small cell lung cancer stage IV 30.15 18.63 8 13486 229 46672339
Hepatitis toxic 28.63 18.63 15 13479 2985 46669583
Skin toxicity 28.55 18.63 16 13478 3638 46668930
Myelosuppression 28.37 18.63 21 13473 7682 46664886
Hepatitis 27.65 18.63 40 13454 32175 46640393
Sarcomatoid carcinoma 27.51 18.63 5 13489 21 46672547
Interstitial lung disease 27.49 18.63 53 13441 53896 46618672
Platelet count decreased 27.43 18.63 77 13417 99947 46572621
Nasopharyngitis 26.54 18.63 6 13488 153992 46518576
Oesophagitis 25.12 18.63 25 13469 13626 46658942
Leukoencephalopathy 24.59 18.63 15 13479 3989 46668579
Tracheal fistula 24.45 18.63 5 13489 43 46672525
EGFR gene mutation 23.32 18.63 6 13488 152 46672416
Leukopenia 23.21 18.63 57 13437 68286 46604282
Skin hyperpigmentation 23.13 18.63 16 13478 5266 46667302
Acute kidney injury 22.89 18.63 131 13363 235724 46436844
Immune-mediated hepatitis 22.70 18.63 8 13486 602 46671966
Sinusitis 22.47 18.63 5 13489 129763 46542805
Lung adenocarcinoma recurrent 22.37 18.63 4 13490 15 46672553
Abdominal discomfort 22.16 18.63 8 13486 151157 46521411
Diverticular perforation 21.81 18.63 13 13481 3318 46669250
Renal salt-wasting syndrome 21.68 18.63 6 13488 202 46672366
Gastrointestinal toxicity 21.06 18.63 14 13480 4317 46668251
Meningitis herpes 20.96 18.63 6 13488 229 46672339
Nephrogenic diabetes insipidus 20.95 18.63 8 13486 755 46671813
Colitis 20.65 18.63 38 13456 37309 46635259
Jaw operation 20.63 18.63 8 13486 787 46671781
Peripheral swelling 20.54 18.63 10 13484 158061 46514507
Weight increased 20.49 18.63 11 13483 164462 46508106
Paronychia 20.39 18.63 14 13480 4552 46668016
Adenocarcinoma 20.28 18.63 11 13483 2348 46670220
Rash maculo-papular 20.21 18.63 32 13462 27842 46644726
Maternal exposure during pregnancy 19.80 18.63 3 13491 102546 46570022
Feeling abnormal 19.41 18.63 6 13488 125054 46547514
Anaplastic lymphoma kinase gene mutation 19.37 18.63 3 13491 3 46672565
Metastases to liver 19.31 18.63 26 13468 19559 46653009
Carcinoembryonic antigen increased 19.27 18.63 9 13485 1400 46671168
Malignant transformation 19.22 18.63 6 13488 309 46672259
Insomnia 19.16 18.63 12 13482 164912 46507656
Transaminases increased 18.94 18.63 31 13463 27730 46644838
Somnolence 18.73 18.63 11 13483 156510 46516058

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 591 16.22 465 22071 71822 29858120
Pancytopenia 327.79 16.22 360 22176 84692 29845250
Thrombocytopenia 212.63 16.22 374 22162 136670 29793272
Interstitial lung disease 198.01 16.22 235 22301 59962 29869980
Neutropenia 190.58 16.22 344 22192 128196 29801746
Anaemia 180.54 16.22 447 22089 207545 29722397
Bone marrow failure 157.94 16.22 150 22386 29635 29900307
Mucosal inflammation 147.46 16.22 146 22390 30348 29899594
Disease progression 139.43 16.22 230 22306 79644 29850298
General physical health deterioration 129.86 16.22 253 22283 99691 29830251
Febrile neutropenia 113.78 16.22 249 22287 106444 29823498
Lung adenocarcinoma 112.41 16.22 57 22479 4042 29925900
Febrile bone marrow aplasia 104.65 16.22 69 22467 8028 29921914
Non-small cell lung cancer 99.75 16.22 51 22485 3679 29926263
Neoplasm progression 90.26 16.22 88 22448 17935 29912007
Pneumonitis 83.30 16.22 103 22433 27351 29902591
Leukopenia 76.28 16.22 145 22391 56014 29873928
Drug ineffective 69.49 16.22 93 22443 340294 29589648
Myelosuppression 63.64 16.22 49 22487 7273 29922669
Pleural effusion 62.62 16.22 158 22378 73908 29856034
Dehydration 61.99 16.22 219 22317 123320 29806622
Completed suicide 59.25 16.22 4 22532 99488 29830454
Enteritis 56.73 16.22 44 22492 6601 29923341
Decreased appetite 56.68 16.22 243 22293 149667 29780275
Aplasia 56.07 16.22 36 22500 4001 29925941
Neutrophil count decreased 50.83 16.22 104 22432 42350 29887592
Immune-mediated adverse reaction 48.99 16.22 17 22519 459 29929483
Drug interaction 48.80 16.22 47 22489 199521 29730421
Vomiting 45.65 16.22 302 22234 219516 29710426
Diarrhoea 45.54 16.22 416 22120 333687 29596255
Metastases to central nervous system 45.02 16.22 40 22496 7244 29922698
Septic shock 44.94 16.22 127 22409 63480 29866462
Haematotoxicity 44.47 16.22 37 22499 6133 29923809
Pulmonary embolism 43.06 16.22 143 22393 77992 29851950
Platelet count decreased 41.58 16.22 174 22362 105955 29823987
Headache 41.09 16.22 46 22490 182260 29747682
Skin toxicity 40.31 16.22 27 22509 3222 29926720
Lung disorder 39.94 16.22 79 22457 31390 29898552
Haemoptysis 39.42 16.22 78 22458 31000 29898942
Superior vena cava syndrome 38.73 16.22 14 22522 427 29929515
Product dose omission issue 37.83 16.22 11 22525 91620 29838322
Nausea 36.54 16.22 362 22174 296595 29633347
Lung cancer metastatic 36.24 16.22 23 22513 2505 29927437
Colitis 35.12 16.22 74 22462 30746 29899196
Overdose 35.04 16.22 10 22526 84327 29845615
Respiratory failure 33.35 16.22 157 22379 100485 29829457
Neutropenic sepsis 33.30 16.22 42 22494 11367 29918575
Fall 32.78 16.22 54 22482 181818 29748124
Off label use 32.65 16.22 308 22228 248982 29680960
Large intestine perforation 32.16 16.22 34 22502 7617 29922325
Pneumothorax 31.41 16.22 49 22487 16144 29913798
Small intestinal perforation 30.89 16.22 18 22518 1681 29928261
Radiation pneumonitis 30.73 16.22 19 22517 1977 29927965
Bradycardia 30.71 16.22 6 22530 65520 29864422
White blood cell count decreased 30.06 16.22 134 22402 83813 29846129
Peripheral swelling 29.90 16.22 5 22531 61069 29868873
Purpura 29.58 16.22 37 22499 9930 29920012
Hiccups 29.57 16.22 36 22500 9398 29920544
Hepatocellular injury 28.83 16.22 61 22475 25410 29904532
Pain in extremity 28.03 16.22 25 22511 110196 29819746
Toxicity to various agents 28.01 16.22 57 22479 177126 29752816
Epistaxis 27.43 16.22 95 22441 52886 29877056
Performance status decreased 27.01 16.22 23 22513 3934 29926008
Sepsis 26.69 16.22 195 22341 146200 29783742
Dyspnoea 26.20 16.22 373 22163 332922 29597020
Pleural mesothelioma malignant 26.18 16.22 7 22529 75 29929867
Rheumatoid nodule 25.79 16.22 16 22520 1674 29928268
Metastases to bone 25.75 16.22 34 22502 9624 29920318
Tubulointerstitial nephritis 25.25 16.22 47 22489 17844 29912098
EGFR gene mutation 24.81 16.22 7 22529 93 29929849
Opsoclonus myoclonus 24.71 16.22 6 22530 42 29929900
Muscle spasms 24.61 16.22 9 22527 64829 29865113
Nasopharyngitis 24.40 16.22 7 22529 58842 29871100
Vasculitis 24.25 16.22 30 22506 7960 29921982
Lung neoplasm malignant 24.23 16.22 42 22494 15090 29914852
Aphthous ulcer 24.13 16.22 22 22514 4119 29925823
Peritonitis 23.97 16.22 51 22485 21324 29908618
Pneumonia 23.87 16.22 368 22168 333938 29596004
Rhabdomyolysis 23.84 16.22 9 22527 63571 29866371
Disseminated intravascular coagulation 23.83 16.22 52 22484 22119 29907823
Gastrointestinal perforation 22.63 16.22 20 22516 3596 29926346
Blood pressure increased 22.62 16.22 13 22523 71915 29858027
Tremor 21.80 16.22 15 22521 75348 29854594
Malignant pleural effusion 21.49 16.22 13 22523 1301 29928641
Renal failure 21.36 16.22 168 22368 128798 29801144
Feeling abnormal 21.33 16.22 8 22528 56748 29873194
Tumour necrosis 20.99 16.22 12 22524 1081 29928861
Mesothelioma 20.45 16.22 9 22527 463 29929479
Cachexia 20.35 16.22 25 22511 6586 29923356
Bicytopenia 20.33 16.22 14 22522 1748 29928194
Lymphangiosis carcinomatosa 20.24 16.22 11 22525 898 29929044
Occipital neuralgia 20.24 16.22 5 22531 38 29929904
Dysphagia 19.90 16.22 90 22446 56608 29873334
Radiation oesophagitis 19.00 16.22 8 22528 369 29929573
Rash 18.90 16.22 224 22312 191665 29738277
Anxiety 18.80 16.22 24 22512 89847 29840095
Myalgia 18.76 16.22 18 22518 76649 29853293
Extremity necrosis 18.74 16.22 13 22523 1642 29928300
Immune-mediated enterocolitis 18.64 16.22 11 22525 1052 29928890
Laryngeal leukoplakia 18.58 16.22 5 22531 55 29929887
Lung adenocarcinoma recurrent 18.58 16.22 3 22533 0 29929942
Insomnia 18.44 16.22 26 22510 93310 29836632
Cardiac failure congestive 18.22 16.22 22 22514 84385 29845557
Oral candidiasis 18.08 16.22 31 22505 11040 29918902
Oesophagitis 17.88 16.22 31 22505 11140 29918802
Nephropathy toxic 17.65 16.22 30 22506 10609 29919333
Diaphragmatic rupture 17.62 16.22 4 22532 20 29929922
Epidermolysis 17.59 16.22 7 22529 279 29929663
Human chorionic gonadotropin increased 17.46 16.22 4 22532 21 29929921
Musculoskeletal stiffness 17.42 16.22 3 22533 35878 29894064
Hypophagia 17.28 16.22 46 22490 22190 29907752
Drug resistance 17.03 16.22 43 22493 20090 29909852
Intestinal perforation 16.83 16.22 26 22510 8493 29921449
Acute kidney injury 16.74 16.22 294 22242 273548 29656394
Hallucination 16.70 16.22 8 22528 49051 29880891
Agitation 16.67 16.22 10 22526 54063 29875879
Maximal voluntary ventilation abnormal 16.50 16.22 3 22533 3 29929939
Arthralgia 16.50 16.22 50 22486 135741 29794201
Retinopathy 16.48 16.22 13 22523 1997 29927945
Lymphangitis 16.42 16.22 8 22528 520 29929422

Pharmacologic Action:

SourceCodeDescription
ATC L01BA04 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
ANTIMETABOLITES
Folic acid analogues
FDA MoA N0000000111 Folic Acid Metabolism Inhibitors
FDA EPC N0000175584 Folate Analog Metabolic Inhibitor
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:35221 antimetabolite
CHEBI has role CHEBI:35610 cytostatic
CHEBI has role CHEBI:50683 7,8-dihydrofolate reductase inhibitors
CHEBI has role CHEBI:63720 ec 2.1.1.45 inhibitors
CHEBI has role CHEBI:63721 glycinamide ribonucleotide formyltransferase inhibitors

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)

None

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
4021417 VUID
N0000148831 NUI
D03828 KEGG_DRUG
150399-23-8 SECONDARY_CAS_RN
4021417 VANDF
C0210657 UMLSCUI
CHEBI:63723 CHEBI
LYA PDB_CHEM_ID
CHEMBL225072 ChEMBL_ID
CHEMBL2360464 ChEMBL_ID
D000068437 MESH_DESCRIPTOR_UI
101068009 PUBCHEM_CID
DB00642 DRUGBANK_ID
6837 IUPHAR_LIGAND_ID
7675 INN_ID
04Q9AIZ7NO UNII
1666923 RXNORM
17856 MMSL
32871 MMSL
48646 MMSL
d05047 MMSL
008494 NDDF
008495 NDDF
409159000 SNOMEDCT_US
411089001 SNOMEDCT_US
735172002 SNOMEDCT_US

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Alimta HUMAN PRESCRIPTION DRUG LABEL 1 0002-7623 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 500 mg INTRAVENOUS NDA 33 sections
Alimta HUMAN PRESCRIPTION DRUG LABEL 1 0002-7640 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 100 mg INTRAVENOUS NDA 33 sections