LORLATINIB ACETATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H19FN6O2.C2H4O2
Molecular Weight	466.4649
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(O)=O.C[C@H]1OC2=CC(=CN=C2N)C3=C(C#N)N(C)N=C3CN(C)C(=O)C4=C1C=C(F)C=C4

InChI

InChIKey=BLNAIBLTPYGILH-RFVHGSKJSA-N

InChI=1S/C21H19FN6O2.C2H4O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12;1-2(3)4/h4-7,9,11H,10H2,1-3H3,(H2,24,25);1H3,(H,3,4)/t11-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	C21H19FN6O2
Molecular Weight	406.413
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	C2H4O2
Molecular Weight	60.052
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.pfizer.com/files/news/esmo/ESMO2016_Pipeline_Fact_Sheet_Lorlatinib.pdf | https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf | https://www.pfizer.com/files/news/asco/Lorlatinib_Fact_Sheet.pdf
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800039198 | http://meetinglibrary.asco.org/content/143329-156

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors. Lorlatinib has in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, 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. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
ALK tyrosine kinase receptor 24 Target ID: CHEMBL4247 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24819116 \| http://www.pfizer.com/files/news/esmo/ESMO2016_Pipeline_Fact_Sheet_Lorlatinib.pdf	Inhibitor 8504	0.07 nM [IC50]
Proto-oncogene tyrosine-protein kinase ROS 5 Target ID: CHEMBL5568 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24819116 \| http://www.pfizer.com/files/news/esmo/ESMO2016_Pipeline_Fact_Sheet_Lorlatinib.pdf	Inhibitor 8504	0.02 nM [IC50]
Leukocyte tyrosine kinase receptor 2 Target ID: CHEMBL5627 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24819116	Inhibitor 8504	2.7 nM [IC50]
Tyrosine-protein kinase FER 2 Target ID: CHEMBL3982 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24819116	Inhibitor 8504	3.3 nM [IC50]
Tyrosine-protein kinase FES 2 Target ID: CHEMBL5455 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24819116	Inhibitor 8504	6.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Anaplastic Large Cell Lymphoma, ALK-Positive 2 Sources: https://clinicaltrials.gov/ct2/show/NCT03505554 https://adisinsight.springer.com/drugs/800039198	Primary	Phase II 1147	Unknown Approved Use Unknown
Non-small cell lung cancer 211 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf https://adisinsight.springer.com/drugs/800039198 https://www.lorbrena.com/	Primary	Approved 8583	Lorbrena Approved Use LORBRENA is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease; or alectinib as the first ALK inhibitor therapy for metastatic disease; or ceritinib as the first ALK inhibitor therapy for metastatic disease . Launch Date 2018
Neuroblastoma 26 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27483357 https://www.ncbi.nlm.nih.gov/pubmed/26554404 https://adisinsight.springer.com/drugs/800039198	Primary	Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
577 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LORLATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
5650 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LORLATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
24 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LORLATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
34% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LORLATINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg 1 times / day multiple, oral Highest studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29074098	unhealthy, 51 years Health Status: unhealthy Age Group: 51 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/29074098	Disc. AE: Cognitive disorder, Aphasia... AEs leading to discontinuation/dose reduction: Cognitive disorder (2 patients) Aphasia (2 patients) Irritability (2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/29074098
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	unhealthy, 53 years (range: 19 - 85 years) Health Status: unhealthy Age Group: 53 years (range: 19 - 85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf	Disc. AE: Respiratory failure, Dyspnea... AEs leading to discontinuation/dose reduction: Respiratory failure (1.4%) Dyspnea (0.7%) Myocardial infarction (0.7%) Cognitive disorder NEC (0.7%) Mood disorder (0.7%) Edema (7%) Hypertriglyceridemia (6%) Peripheral neuropathy (5%) Cognitive disorder NEC (4.4%) Lipase increased (3.7%) Hypercholesterolemia (3.4%) Mood disorder (3.1%) Dyspnea (2.7%) Pneumonia (2.7%) Hypertension (2%) Edema (6%) Peripheral neuropathy (4.7%) Cognitive disorder NEC (4.1%) Mood disorder (3.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf	unhealthy, 53 years (range: 19 - 85 years) Health Status: unhealthy Age Group: 53 years (range: 19 - 85 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf	Disc. AE: Acute leukemia, Brain compression... AEs leading to discontinuation/dose reduction: Acute leukemia (0.3%) Brain compression (0.3%) Embolism (0.3%) Hallucinations (0.3%) Headache (0.3%) Hydrocephalus (0.3%) Hypoxia (0.3%) Leukocytosis (0.3%) Loss of consciousness (0.3%) Lung infection (0.3%) Mental status changes (0.3%) Parkinsonian gait (0.3%) Peripheral swelling (0.3%) Thrombocytopenia (0.3%) Tinnitus (0.3%) Vomiting (0.3%) Hypertriglyceridemia (1.7%) Arthralgia (1%) Dizziness (1%) Hallucinations (1%) Weight increased (1%) Blood amylase increased (1.7%) Diarrhea (1.7%) Fatigue (1.7%) Asthenia (1.7%) Dizziness (1.4%) Fall (1.4%) Hyperglycemia (1.4%) Pyrexia (1.4%) ALT increased (1%) Anemia (1%) Arthralgia (1%) Atrial fibrillation (1%) Back pain (1%) Ejection fraction decreased (1%) Mental status changes (1%) Pericardial effusion (1%) Pleural effusion (1%) Acute respiratory failure (1%) Respiratory failure (1%) Vomiting (1%) Weight increased (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 inhibitor 2252 substrate 1946	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 CYP1A2 2153 CYP2B6 926 CYP2C19 2057 CYP2C8 1057 MATE1 415 MATE2 267 OAT1 725 OAT3 747 OATP1B1 1079 OATP1B3 961 OCT1 620 OCT2 779 P-gp 1741 UGT1A1 246 UGT1A4 98 UGT1A6 136 UGT1A9 148 UGT2B7 197 Nav1.5 116	CYP2C19 1119 CYP2C8 810 CYP3A5 446 UGT1A3 470 UGT1A4 399	CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
MATE2 267	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
UGT1A4 100	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
UGT1A6 171	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
UGT1A9 155	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
UGT2B7 210	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	no
PXR 51	activator 342 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 85.0	yes [EC50 2.85 uM]	yes (co-administration study) Comment: rifampin reduced mean lorlatinib AUC by 85% and Cmax by 76% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 85.0
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 85.0	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 85.0	yes
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0	yes	yes (co-administration study) Comment: lorlatinib reduced midazolam AUC by 64% and Cmax by 50% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 14.0

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13.0	minor
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13.0	minor
CYP3A5 446	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13.0	minor
UGT1A3 470	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13.0	minor
UGT1A4 399	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13.0	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13, 14	yes	yes (co-administration study) Comment: rifampin reduced mean lorlatinib AUC by 85% and Cmax by 76%; Itraconazole increased lorlatinib AUC by 42% and Cmax by 24% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf Page: 13, 14

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 119	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 42, 49
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210868Orig1s000MultidisciplineR.pdf Page: 42, 51

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:143117	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:143117
ChemicalBook	CB02716543	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB02716543
MolPort	MolPort-035-789-724	https://www.molport.com/shop/molecule-link/MolPort-035-789-724
ZINC	ZINC000098208524	http://zinc15.docking.org/substances/ZINC000098208524

PubMed

Title	Date	PubMed
Tackling ALK in non-small cell lung cancer: the role of novel inhibitors.	2016 Jun	27413712
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.	2016 Oct	27432227
The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.	2016 Sep 1	27483357

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage is 100 mg orally once daily.

Route of Administration: Oral

In Vitro Use Guide

Mutant ALKG1128A, ALKF1174L, ALKR1192P, ALKF1245C and ALKR1275Q responded to PF-06463922 with IC50 values similar to that of wild-type, two mutants – ALKI1171N and ALKY1278S – were more resistant, with 4- and 2.8-fold (3.21 nM and 2.27 nM) respectively of the IC50 of wild-type ALK kinase.

Substance Class	Chemical Created by `admin` on `Wed Apr 02 03:58:39 GMT 2025` Edited by `admin` on `Wed Apr 02 03:58:39 GMT 2025`
Record UNII	TE9WI16FEU
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PF-06463922 ACETATE

Preferred Name

English

LORLATINIB ACETATE

Common Name

English

2H-4,8-METHENOPYRAZOLO(4,3-H)(2,5,11)BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE, 7-AMINO-12-FLUORO-10,15,16,17-TETRAHYDRO-2,10,16-TRIMETHYL-15-OXO-, (10R)-, ACETATE

Systematic Name

English

Code System Code Type Description

FDA UNII

TE9WI16FEU

Created by admin on Wed Apr 02 03:58:39 GMT 2025 , Edited by admin on Wed Apr 02 03:58:39 GMT 2025

PRIMARY

CAS

1924207-18-0

Created by admin on Wed Apr 02 03:58:39 GMT 2025 , Edited by admin on Wed Apr 02 03:58:39 GMT 2025

PRIMARY

PUBCHEM

124203822

Created by admin on Wed Apr 02 03:58:39 GMT 2025 , Edited by admin on Wed Apr 02 03:58:39 GMT 2025

PRIMARY

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ACTIVE MOIETY

Details

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Approved Use

Approved Use

Launch Date

Approved Use

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator