LUMACAFTOR

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H18F2N2O5
Molecular Weight	452.4069
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(NC(=O)C2(CC2)C3=CC4=C(OC(F)(F)O4)C=C3)N=C1C5=CC=CC(=C5)C(O)=O

InChI

InChIKey=UFSKUSARDNFIRC-UHFFFAOYSA-N

InChI=1S/C24H18F2N2O5/c1-13-5-8-19(27-20(13)14-3-2-4-15(11-14)21(29)30)28-22(31)23(9-10-23)16-6-7-17-18(12-16)33-24(25,26)32-17/h2-8,11-12H,9-10H2,1H3,(H,29,30)(H,27,28,31)

HIDE SMILES / InChI

Molecular Formula	C24H18F2N2O5
Molecular Weight	452.4069
Charge	0
Count

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

Description
Sources: http://adisinsight.springer.com/drugs/800027666
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206038Orig1s000lbl.pdf https://newdrugapprovals.org/tag/lumacaftor/

Lumacaftor (VX-809) is an investigational drug developed by the Massachusetts-based pharmaceutical company Vertex for the treatment of patients who suffer from cystic fibrosis (CF) and have the F508del mutation in the CF transmembrane conductance regulator (CFTR). Currently, lumacaftor is approved by the U.S. FDA as a combined oral treatment for CF in combination with Kalydeco (ivacaftor). Lumacaftor is commercialized by Vertex under the brand name Orkambi, and Kalydeco was approved in the United States in 2012. The lumacaftor/Kalydeco combo was approved by the FDA in July 2015 for patients ages 12 and older, while the use of lumacaftor alone is still being studied by Vertex. The mechanism of action of lumacaftor is based on the interference with the F508 CFTR. The chronic disease is caused by a mutation in the gene that controls the salt transportation in the cells, resulting in thick, sticky mucus in the respiratory, digestive, and reproductive systems. To address that genetic defect, lumacaftor helps correct the mutated genes with a novel therapeutic approach. Both lumicaftor and kalydeco work by correcting the misfolded CFTR protein, the root cause of the F508del mutation, which led to the approval of the combined treatment by the FDA. However, while kalydeco alone is also approved by the FDA, the use of lumacftor alone has not yet been approved.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
F508del-CFTR 1 Target ID: F508del-CFTR Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206038Orig1s000lbl.pdf	Chaperone 14
Cytochrome P450 3A 22 Target ID: CHEMBL2364675 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27821435	Activator 1430

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cystic fibrosis (CF) in patients homozygous for the F508del mutation in the CFTR gene 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206038Orig1s000lbl.pdf	Primary		Approved 8429	Orkambi Approved Use ORKAMBI is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Launch Date 2015

C_max

Value	Dose	Co-administered	Analyte	Population
25 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206038s010lbl.pdf	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LUMACAFTOR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
198 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206038s010lbl.pdf	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LUMACAFTOR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
25.2 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206038s010lbl.pdf	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LUMACAFTOR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206038s010lbl.pdf	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LUMACAFTOR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg 1 times / day steady, oral Dose: 200 mg, 1 times / day Route: oral Route: steady Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21825083	unhealthy, 25 years(range: 18–42 years) n = 19 Health Status: unhealthy Age Group: 25 years(range: 18–42 years) Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/21825083	Other AEs: Cough, Headache... Other AEs: Cough (52.6%) Headache (26.3%) Rales (15.8%) Productive cough (31.6%) Dyspnoea (21.1%) Respiratory tract disorders NEC (21.1%) Fatigue (15.8%) Fever (26.3%) Nasal congestion (11.8%) Oropharyngeal pain (10.5%) Sinus congestion (5.3%) Respiration abnormal (21.1%) Haemoptysis (10.5%) Constipation (5.3%) Abdominal pain (5.3%) Myalgia (5.3%) Post-tussive vomiting (5.3%) Nausea (5.3%) Nasopharyngitis (10.5%) Dizziness (5.3%) Back pain (5.3%) Abdominal pain upper (10.5%) Sputum abnormal (5.3%) Epistaxis (10.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/21825083

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 CYP2B6 810 CYP2C8 911 P-gp 1461 OATP1B1 788 OATP1B3 706	P-gp 1537 OATP1B1 406 OATP1B3 350	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=6 Page: 6.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=6 Page: 6.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=6 Page: 6.0	no
OATP1B1 803	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	yes
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	yes
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	yes
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204153s004s005lbl.pdf#page=5 Page: 5.0	yes
P-gp 1650	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	yes

Drug as victim

Target	Modality	Activity
OATP1B1 406	substrate 3367 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	no
OATP1B3 350	substrate 3367 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	no
P-gp 1537	substrate 3367 Sources: https://www.ema.europa.eu/en/documents/assessment-report/orkambi-epar-public-assessment-report_en.pdf#page=22 Page: 22.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204153Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204153Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204153Orig1s000PharmR.pdf#page=4 Page: 4.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90951	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90951
ChemicalBook	CB32489655	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32489655
MolPort	MolPort-009-198-874	https://www.molport.com/shop/molecule-link/MolPort-009-198-874
Selleck Chemicals	VX-809	http://www.selleckchem.com/products/VX-809.html
ZINC	ZINC000064033452	http://zinc15.docking.org/substances/ZINC000064033452
eMolecules	32278074	https://www.emolecules.com/cgi-bin/more?vid=32278074

PubMed

Title	Date	PubMed
Mechanism-based corrector combination restores ΔF508-CFTR folding and function.	2013 Jul	23666117
VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.	2013 Oct	23924900
A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial.	2014 Jul	24973281

Patents

Sample Use Guides

In Vivo Use Guide

Adults and pediatric patients age 12 years and older: two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours with fat-containing food.

Route of Administration: Oral

In Vitro Use Guide

Acute pretreatment of temperature-rescued F508del-CFTR in BHK Cells with 3uM Lumacaftor (VX-809) promotes channel activation

Substance Class	Chemical Created by `admin` on `Fri Dec 15 20:15:38 GMT 2023` Edited by `admin` on `Fri Dec 15 20:15:38 GMT 2023`
Record UNII	EGP8L81APK
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

LUMACAFTOR

Official Name

English

LUMACAFTOR [ORANGE BOOK]

Common Name

English

VRT826809

Code

English

VX-809

Code

English

VRT-826809

Code

English

Lumacaftor [WHO-DD]

Common Name

English

LUMACAFTOR [MI]

Common Name

English

VX809

Code

English

3-(6-(1-(2,2-DIFLUORO-1,3-BENZODIOXOL-5-YL)CYCLOPROPANE-1-CARBOXAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOIC ACID

Systematic Name

English

ORKAMBI COMPONENT LUMACAFTOR

Brand Name

English

BENZOIC ACID, 3-(6-(((1-(2,2-DIFLUORO-1,3-BENZODIOXOL-5-YL)CYCLOPROPYL)CARBONYL)AMINO)-3-METHYL-2-PYRIDINYL)-

Common Name

English

3-(6-(1-(2,2-DIFLUOROBENZO(D) (1,3)DIOXYL-5-YL)CYCLOPROPANECARBOXAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOIC ACID

Systematic Name

English

lumacaftor [INN]

Common Name

English

LUMACAFTOR COMPONENT OF ORKAMBI

Brand Name

English

LUMACAFTOR [USAN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

301610