lorlatinib 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | BioActivity |

Stem definitionDrug idCAS RN
tyrosine kinase inhibitors 5302 1454846-35-5

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • lorlatinib
  • lorbrena
  • PF-06463922
  • PF-6463922
  • lorviqua
Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.
  • Molecular weight: 406.42
  • Formula: C21H19FN6O2
  • CLOGP: 2.07
  • LIPINSKI: 0
  • HAC: 8
  • HDO: 1
  • TPSA: 110.06
  • ALOGS: -3.57
  • ROTB: 0
  • Status: ONP
    • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

DoseUnitRoute
0.10 g O

ADMET properties:

PropertyValueReference
S (Water solubility) 0.17 mg/mL Bocci G, Oprea TI, Benet LZ
BDDCS (Biopharmaceutical Drug Disposition Classification System) 2 Bocci G, Oprea TI, Benet LZ

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
azlogd74 LogD at pH 7.4 1.806 High 1
caco2-efflux Caco-2 efflux ratio (BA/AB) 0.817 High 1
caco2-intrinsic-papp Caco-2 intrinsic apparent permeability 66.834 10^-6 cm/s High 1
dh-clint Dog hepatocyte intrinsic clearance 2.649 uL/min/10^6 cells High 1
dppb Dog plasma protein binding (% unbound) 39.290 % High 1
fcs-ppb Fetal calf serum protein binding (% unbound) 61.370 % High 1
herg hERG pIC50 4.329 pIC50 High 1
hh-clint Human hepatocyte intrinsic clearance 1.216 uL/min/10^6 cells High 1
hlm-clint Human liver microsomal intrinsic clearance 6.237 uL/min/mg protein High 1
hppb Human plasma protein binding (% unbound) 33.330 % High 1
kinase-safety-class ACVR2B,AURKA,AXL,CAMK2B,CAMK2D,CDK9,CLK4,CSF1R,DYRK1A,DYRK1B,EGFR,EIF2AK3,ERBB2,FLT3,GAK,GRK2,GSK3B,IRAK1,IRAK3,ITK,KDR,MAP3K21,MAP4K1,MAP4K3,MAP4K5,NTRK1,PDK1,PDK2,PDK4,PIK3CA,PIK3CB,PIK3CD,PIK3CG,PRKDC,SIK2,SIK3,STK17A,TGFBR1,TYRO3 39
kinase-selectivity-class ACVR2B,ALK,AXL,CAMK2D,CLK4,EGFR,FLT3,IRAK1,IRAK3,LRRK2,MAP3K7,MAP4K1,MINK1,NTRK1,PDK1,SIK2,TNIK,TNK1 18
mdck-mdr1-bcrp-efflux MDCK-MDR1-BCRP efflux ratio 1.675 High 1
mdck-mdr1-efflux MDCK-MDR1 efflux ratio 1.483 High 1
mh-clint Mouse hepatocyte intrinsic clearance 6.761 High 1
mppb Mouse plasma protein binding (% unbound) 38.960 High 1
nih-mdck-mdr1-efflux NIH MDCK-MDR1 efflux ratio 5.321 High 1
pfas-class PFAS structural alert (1 = True, 0 = False) 0
pppb Pig plasma protein binding (% unbound) 51.780 % High 1
rat-kpuu-brain Rat brain Kpuu 0.186 % High 1
rh-clint Rat hepatocyte intrinsic clearance 2.042 uL/min/10^6 cells High 1
rh-fuinc Rat hepatocyte fraction unbound in incubation 85.850 % High 1
rppb Rat plasma protein binding (% unbound) 34.570 % High 1
solubility-dd Solubility at pH 7.4 in DMSO 414 uM High 1

Approvals:

DateAgencyCompanyOrphan
Sept. 21, 2018 PMDA Pfizer Japan Inc
Sept. 21, 2018 FDA PFIZER INC
June 6, 2019 EMA PFIZER EUROPE MA EEIG

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
Neoplasm progression 658.14 28.05 189 4309 44297 90579652
Hallucination 249.70 28.05 101 4397 65858 90558091
Death 244.20 28.05 192 4306 456359 90167590
Hypertriglyceridaemia 227.65 28.05 57 4441 7832 90616117
Hyperlipidaemia 183.45 28.05 61 4437 22855 90601094
Hypercholesterolaemia 172.92 28.05 89 4409 100803 90523146
Hallucination, auditory 145.90 28.05 47 4451 15928 90608021
Hallucination, visual 106.99 28.05 41 4457 23051 90600898
Blood triglycerides increased 95.77 28.05 33 4465 13728 90610221
Oedema peripheral 91.22 28.05 86 4412 257829 90366120
Cognitive disorder 90.14 28.05 51 4447 69356 90554593
Oedema 89.02 28.05 76 4422 200219 90423730
Nervous system disorder 81.29 28.05 33 4465 21560 90602389
Dyslipidaemia 81.20 28.05 27 4471 10080 90613869
Pericardial effusion 76.25 28.05 37 4461 36796 90587153
Pleural effusion 74.60 28.05 54 4444 111937 90512012
Low density lipoprotein increased 70.58 28.05 23 4475 8062 90615887
Weight increased 63.37 28.05 90 4408 417837 90206112
Metastases to central nervous system 63.25 28.05 26 4472 17516 90606433
Neuropathy peripheral 62.88 28.05 53 4445 136917 90487032
Blood cholesterol increased 59.77 28.05 62 4436 207950 90415999
Disease progression 56.74 28.05 53 4445 156562 90467387
Persecutory delusion 53.37 28.05 15 4483 3193 90620756
Lipids increased 50.50 28.05 12 4486 1320 90622629
Drug resistance 38.48 28.05 22 4476 30427 90593522
Focal segmental glomerulosclerosis 37.00 28.05 10 4488 1841 90622108
Speech disorder 34.99 28.05 24 4474 45561 90578388
Mood altered 34.79 28.05 17 4481 17127 90606822
Second primary malignancy 32.77 28.05 14 4484 10364 90613585
Psychotic disorder 32.74 28.05 20 4478 31210 90592739
Mental disorder 32.11 28.05 20 4478 32298 90591651
Radiation necrosis 30.45 28.05 7 4491 666 90623283
Memory impairment 29.07 28.05 42 4456 197202 90426747

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
Neoplasm progression 538.99 28.89 168 3643 28832 42588692
Hallucination 167.96 28.89 88 3723 57419 42560105
Hypercholesterolaemia 140.12 28.89 50 3761 12799 42604725
Death 126.08 28.89 180 3631 471005 42146519
Hyperlipidaemia 95.87 28.89 44 3767 21472 42596052
Oedema 83.39 28.89 54 3757 51947 42565577
Hypertriglyceridaemia 79.56 28.89 31 3780 10095 42607429
Blood cholesterol increased 69.66 28.89 38 3773 26703 42590821
Cognitive disorder 66.11 28.89 40 3771 34132 42583392
Metastases to central nervous system 58.40 28.89 25 3786 10330 42607194
Weight increased 55.95 28.89 58 3753 107925 42509599
Disease progression 51.97 28.89 64 3747 143592 42473932
Hallucination, visual 44.26 28.89 26 3785 20994 42596530
Oedema peripheral 43.46 28.89 57 3754 136019 42481505
Psychotic disorder 41.12 28.89 28 3783 29180 42588344
Blood triglycerides increased 39.75 28.89 22 3789 15874 42601650
Pleural effusion 39.54 28.89 46 3765 97120 42520404
Malignant neoplasm progression 38.68 28.89 48 3763 108352 42509172
Nervous system disorder 38.13 28.89 22 3789 17173 42600351
Dyslipidaemia 38.00 28.89 18 3793 9400 42608124
Memory impairment 35.43 28.89 32 3779 50190 42567334
Pericardial effusion 34.10 28.89 25 3786 29250 42588274
Low density lipoprotein increased 33.76 28.89 14 3797 5341 42612183
Pneumonitis 32.25 28.89 28 3783 41690 42575834
Lipids increased 30.89 28.89 9 3802 1203 42616321
Carpal tunnel syndrome 30.00 28.89 13 3798 5526 42611998

FDA Adverse Event Reporting System (Geriatric)

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
Neoplasm progression 1052.01 25.48 317 7166 64278 110517538
Hallucination 281.15 25.48 137 7346 101295 110480521
Death 276.22 25.48 284 7199 698585 109883231
Hypertriglyceridaemia 264.95 25.48 80 7403 16074 110565742
Hypercholesterolaemia 264.72 25.48 127 7356 90710 110491106
Hyperlipidaemia 223.76 25.48 86 7397 35762 110546054
Hallucination, auditory 138.92 25.48 56 7427 26341 110555475
Oedema 136.18 25.48 113 7370 209863 110371953
Hallucination, visual 117.09 25.48 56 7427 39549 110542267
Dyslipidaemia 116.61 25.48 43 7440 15922 110565894
Cognitive disorder 116.59 25.48 73 7410 87438 110494378
Oedema peripheral 115.50 25.48 126 7357 328534 110253282
Blood triglycerides increased 103.05 25.48 44 7439 23882 110557934
Disease progression 102.57 25.48 103 7380 243931 110337885
Metastases to central nervous system 101.72 25.48 43 7440 22774 110559042
Pleural effusion 101.57 25.48 89 7394 177620 110404196
Pericardial effusion 87.10 25.48 52 7431 57165 110524651
Blood cholesterol increased 81.29 25.48 80 7403 184705 110397111
Nervous system disorder 76.33 25.48 39 7444 31682 110550134
Lipids increased 75.36 25.48 19 7464 1954 110579862
Weight increased 74.75 25.48 115 7368 419529 110162287
Low density lipoprotein increased 71.56 25.48 27 7456 10639 110571177
Neuropathy peripheral 68.60 25.48 72 7411 179205 110402611
Malignant neoplasm progression 61.30 25.48 67 7416 174500 110407316
Memory impairment 49.92 25.48 64 7419 196880 110384936
Radiation necrosis 46.80 25.48 11 7472 843 110580973
Pneumonitis 45.00 25.48 39 7444 76492 110505324
Psychotic disorder 42.81 25.48 32 7451 50905 110530911
Persecutory delusion 42.47 25.48 16 7467 6275 110575541
Speech disorder 41.61 25.48 34 7449 61535 110520281
Mental disorder 40.95 25.48 28 7455 38763 110543053
Off label use 40.61 25.48 204 7279 1499981 109081835
Second primary malignancy 34.37 25.48 19 7464 18049 110563767
Irritability 33.56 25.48 27 7456 47782 110534034
Affective disorder 33.52 25.48 16 7467 11225 110570591
Pulmonary toxicity 31.95 25.48 18 7465 17728 110564088
Drug resistance 31.67 25.48 28 7455 56346 110525470
Carpal tunnel syndrome 30.42 25.48 19 7464 22591 110559225
Focal segmental glomerulosclerosis 29.65 25.48 11 7472 4134 110577682
Metastases to liver 29.21 25.48 22 7461 35364 110546452
Hallucinations, mixed 27.84 25.48 13 7470 8680 110573136
Pulmonary embolism 26.45 25.48 50 7433 214424 110367392

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

SourceCodeDescription
ATC L01ED05 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
PROTEIN KINASE INHIBITORS
Anaplastic lymphoma kinase (ALK) inhibitors
FDA MoA N0000175082 Kinase Inhibitors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000187064 Cytochrome P450 2B6 Inducers
FDA MoA N0000190111 Organic Anion Transporter 3 Inhibitors
FDA MoA N0000190113 Breast Cancer Resistance Protein Inhibitors
FDA MoA N0000190118 Cytochrome P450 3A Inducers
FDA MoA N0000191264 P-Glycoprotein Inducers
FDA MoA N0000191265 Organic Cation Transporter 1 Inhibitors
FDA MoA N0000191423 Multidrug and Toxin Extrusion Transporter 1 Inhibitors
CHEBI has role CHEBI:35610 antineoplastic agent
CHEBI has role CHEBI:62434 EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor
CHEBI has role CHEBI:231911 renoprotective agent

Related Drugs by ATC class:

L01ED Anaplastic lymphoma kinase (ALK) inhibitors 4 drugs
alectinibbrigatinibceritinibcrizotinib

Drug Use | Suggest Off label Use Form| |View source of the data|

DiseaseRelationSNOMED_IDDOID
Non-small cell lung cancer indication 254637007 DOID:3908
ALK fusion gene-positive non-small-cell lung cancer indication 830151004




🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 5.76 Basic

Orange Book patent data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
100MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL 10420749 July 27, 2036 TREATMENT OF ADULT PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHOSE TUMORS ARE ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDA-APPROVED TEST
100MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL 10420749 July 27, 2036 TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER, PROGRESSED ON: CRIZOTINIB + AT LEAST 1 OTHER ALK INHIBITOR FOR METASTATIC DISEASE; OR ALECTINIB, OR CERITINIB AS FIRST ALK INHIBITOR FOR METASTATIC DISEASE.
25MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL 10420749 July 27, 2036 TREATMENT OF ADULT PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHOSE TUMORS ARE ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDA-APPROVED TEST
25MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL 10420749 July 27, 2036 TREATMENT OF ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE METASTATIC NON-SMALL CELL LUNG CANCER, PROGRESSED ON: CRIZOTINIB + AT LEAST 1 OTHER ALK INHIBITOR FOR METASTATIC DISEASE; OR ALECTINIB, OR CERITINIB AS FIRST ALK INHIBITOR FOR METASTATIC DISEASE.

Orange Book exclusivity data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
100MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL March 3, 2028 TREATMENT OF ADULT PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHOSE TUMORS ARE ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDA-APPROVED TEST, EXCLUDING PATIENTS WHOSE DISEASE HAS PROGRESSED ON CRIZOTINIB AND AT LEAST ONE OTHER ALK INHIBITOR FOR METASTATIC DISEASE; OR ALECTINIB OR CERITINIB AS THE FIRST ALK INHIBITOR THERAPY FOR METASTATIC DISEASE
25MG LORBRENA PFIZER N210868 Nov. 2, 2018 RX TABLET ORAL March 3, 2028 TREATMENT OF ADULT PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) WHOSE TUMORS ARE ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE AS DETECTED BY AN FDA-APPROVED TEST, EXCLUDING PATIENTS WHOSE DISEASE HAS PROGRESSED ON CRIZOTINIB AND AT LEAST ONE OTHER ALK INHIBITOR FOR METASTATIC DISEASE; OR ALECTINIB OR CERITINIB AS THE FIRST ALK INHIBITOR THERAPY FOR METASTATIC DISEASE

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])		Mechanism
action		Bioact sourceMoA source
Tyrosine-protein kinase Fes/Fps Kinase INHIBITOR IC50 8.22 SCIENTIFIC LITERATURE DRUG LABEL
BDNF/NT-3 growth factors receptor Kinase INHIBITOR IC50 7.64 SCIENTIFIC LITERATURE DRUG LABEL
Protein-tyrosine kinase 2-beta Kinase INHIBITOR IC50 7.85 SCIENTIFIC LITERATURE DRUG LABEL
NT-3 growth factor receptor Kinase INHIBITOR IC50 7.34 SCIENTIFIC LITERATURE DRUG LABEL
Leukocyte tyrosine kinase receptor Kinase INHIBITOR IC50 8.57 SCIENTIFIC LITERATURE DRUG LABEL
ALK tyrosine kinase receptor Kinase INHIBITOR Ki 9.96 SCIENTIFIC LITERATURE DRUG LABEL
Proto-oncogene tyrosine-protein kinase ROS Kinase INHIBITOR IC50 9.30 SCIENTIFIC LITERATURE DRUG LABEL
Focal adhesion kinase 1 Kinase INHIBITOR IC50 7.77 SCIENTIFIC LITERATURE DRUG LABEL
High affinity nerve growth factor receptor Kinase INHIBITOR IC50 7.62 SCIENTIFIC LITERATURE DRUG LABEL
Tyrosine-protein kinase Fer Kinase INHIBITOR IC50 8.48 SCIENTIFIC LITERATURE DRUG LABEL
Activated CDC42 kinase 1 Kinase INHIBITOR IC50 7.77 SCIENTIFIC LITERATURE DRUG LABEL
Tyrosine-protein kinase JAK2 Kinase Ki 6.28 CHEMBL
Tyrosine-protein kinase FRK Kinase IC50 7.28 CHEMBL
Activin receptor type-1 Kinase IC50 7.54 CHEMBL
Epidermal growth factor receptor Kinase Ki 7.25 CHEMBL

External reference:

IDSource
OSP71S83EU UNII
4037975 VANDF
C4080091 UMLSCUI
CHEBI:143117 CHEBI
53P PDB_CHEM_ID
5P8 PDB_CHEM_ID
QB4 PDB_CHEM_ID
CHEMBL3286830 ChEMBL_ID
71731823 PUBCHEM_CID
DB12130 DRUGBANK_ID
D11012 KEGG_DRUG
10278 INN_ID
C000590786 MESH_SUPPLEMENTAL_RECORD_UI
7476 IUPHAR_LIGAND_ID
782976007 SNOMEDCT_US
782995000 SNOMEDCT_US
296337 MMSL
35471 MMSL
d09047 MMSL
017834 NDDF
2103164 RXNORM
OSP71S83EU INXIGHT DRUGS

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Lorbrena HUMAN PRESCRIPTION DRUG LABEL 1 0069-0227 TABLET, FILM COATED 25 mg ORAL NDA 31 sections
Lorbrena HUMAN PRESCRIPTION DRUG LABEL 1 0069-0231 TABLET, FILM COATED 100 mg ORAL NDA 31 sections
Lorbrena HUMAN PRESCRIPTION DRUG LABEL 1 63539-927 TABLET, FILM COATED 25 mg ORAL NDA 31 sections