Identification

Name
Lumacaftor
Accession Number
DB09280
Type
Small Molecule
Groups
Approved
Description

Lumacaftor is a drug used in combination with Ivacaftor as the fixed dose combination product Orkambi for the management of Cystic Fibrosis (CF) in patients aged 6 years and older. Cystic Fibrosis is an autosomal recessive disorder caused by one of several different mutations in the gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a transmembrane ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Mutations in the CFTR gene result in altered production, misfolding, or function of the CFTR protein and consequently abnormal fluid and ion transport across cell membranes [3, 4]. As a result, CF patients produce a thick, sticky mucus that clogs the ducts of organs where it is produced making patients more susceptible to infections, lung damage, pancreatic insufficiency, and malnutrition [5]. Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR proteins, preventing misfolding and resulting in increased processing and trafficking of mature protein to the cell surface.

Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, increased weight gain, and improvements in CF symptoms [Label]. This data has been heavily scrutinized, however, with clinical trials showing only modest improvements despite a hefty yearly cost of $259,000 for Orkambi [8]. Improvements in lung function (ppFEV1) were found to be statistically significant, but minimal, with only a 2.6-3.0% change from baseline with more than 70% of patients failing to achieve an absolute improvement of at least 5% [8, 9].

A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR, or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes [6]. When used in combination with Ivacaftor as the fixed dose combination product Orkambi, lumacaftor is specific for the management of CF in patients with delta-F508 mutations as it acts as a protein-folding chaperone, aiding the conformational stability of the mutated CFTR protein. Consequently, lumacaftor increases successful production of CFTR ion channels and the total number of receptors available for use at the cell membrane for fluid and ion transport [2]. The next most common mutation, G551D, affecting 4-5% of CF patients worldwide, is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered [7]. Treatment of patients with G551D and other rarer missense mutations is usually managed with Ivacaftor (Kalydeco), as it aids with altered gating mechanisms by potentiating channel opening probability of CFTR protein.

Prior to the development of lumacaftor and Ivacaftor (Kalydeco), management of CF primarily involved therapies for the control of infections, nutritional support, clearance of mucus, and management of symptoms rather than improvements in the underlying disease process. Approved for use by the Food and Drug Administration in July 2015 and by Health Canada in January 2016, Orkambi was the first combination product approved for the management of Cystic Fibrosis with delta-F508 mutations.

Ivacaftor is manufactured and distributed by Vertex Pharmaceuticals.

Structure
Thumb
Synonyms
  • 3-(6-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic acid
  • lumacaftor
External IDs
VRT 826809 / VRT-826809 / VX 809 / VX-809
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
OrkambiLumacaftor (200 mg) + Ivacaftor (125 mg)TabletOralVertex Pharmaceuticals Incorporated2016-01-27Not applicableCanada
OrkambiLumacaftor (200 mg) + Ivacaftor (125 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiLumacaftor (150 mg/1) + Ivacaftor (188 mg/1)GranuleOralVertex Pharmaceuticals Incorporated2018-08-14Not applicableUs
OrkambiLumacaftor (200 mg/1) + Ivacaftor (125 mg/1)Tablet, film coatedOralVertex Pharmaceuticals Incorporated2015-07-06Not applicableUs
OrkambiLumacaftor (200 mg) + Ivacaftor (125 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiLumacaftor (100 mg/1) + Ivacaftor (125 mg/1)GranuleOralVertex Pharmaceuticals Incorporated2018-08-14Not applicableUs
OrkambiLumacaftor (100 mg) + Ivacaftor (125 mg)TabletOralVertex Pharmaceuticals Incorporated2017-05-03Not applicableCanada
OrkambiLumacaftor (200 mg) + Ivacaftor (125 mg)Tablet, film coatedOralVertex Pharmaceuticals (Europe) Ltd2015-11-19Not applicableEu
OrkambiLumacaftor (100 mg/1) + Ivacaftor (125 mg/1)Tablet, film coatedOralVertex Pharmaceuticals Incorporated2016-10-03Not applicableUs
Categories
UNII
EGP8L81APK
CAS number
936727-05-8
Weight
Average: 452.414
Monoisotopic: 452.118378014
Chemical Formula
C24H18F2N2O5
InChI Key
UFSKUSARDNFIRC-UHFFFAOYSA-N
InChI
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)
IUPAC Name
3-{6-[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropaneamido]-3-methylpyridin-2-yl}benzoic acid
SMILES
CC1=CC=C(NC(=O)C2(CC2)C2=CC=C3OC(F)(F)OC3=C2)N=C1C1=CC(=CC=C1)C(O)=O

Pharmacology

Indication

When given in combination with Ivacaftor as the fixed dose combination product Orkambi, lumacaftor is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene [Label].

Associated Conditions
Pharmacodynamics

Results from clinical trials indicated that treatment with Orkambi (lumacaftor/ Ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life [Label].

Orkambi was not found to increase the QTc interval to any clinically relevant extent [Label].

Mechanism of action

Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR, resulting in increased processing and trafficking of mature protein to the cell surface [Label]. More specifically, lumacaftor acts as a protein-folding chaperone, preventing misfolding of CFTR ion channels and consequent destruction during processing in the endoplasmic reticulum.

TargetActionsOrganism
ACystic fibrosis transmembrane conductance regulator
modulator
Human
Absorption

Following administration of Orkambi (lumacaftor/Ivacaftor) with fat containing foods, peak plasma concentrations were reached at 4 hours (Tmax). It's recommended that Orkambi should be taken with fat-containing foods as they increase absorption of lumacaftor by approximately 2-fold, and[DB08820 by 3-fold [Label].

Volume of distribution

Following oral administration of 200 mg of lumacaftor every 24 hours to cystic fibrosis patients in a fed state for 28 days, the mean (+/-SD) for apparent volumes of distribution was 86.0 (69.8) L [Label].

Protein binding

Lumacaftor is extensively protein bound in the plasma (99%), and binds primarily to albumin [Label].

Metabolism

Lumacaftor is mostly excreted unchanged in the feces and is not extensively metabolized. When metabolism does occur, oxidation and glucuronidation are the main processes involved [Label].

Route of elimination

Lumacaftor is primarily excreted unchanged in the feces (51%). A minimal amount of the parent compound and its metabolites are excreted in the urine [Label].

Half life

The half-life of lumacaftor is approximately 26 hours [Label].

Clearance

The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr [Label].

Toxicity

The most common side effects (occuring in >5% of patients during clinical trials) associated with the use of Orkambi include dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza [Label].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe serum concentration of 16-Bromoepiandrosterone can be decreased when it is combined with Lumacaftor.
19-norandrostenedioneThe serum concentration of 19-norandrostenedione can be decreased when it is combined with Lumacaftor.
5-androstenedioneThe serum concentration of 5-androstenedione can be decreased when it is combined with Lumacaftor.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Lumacaftor.
AbirateroneThe serum concentration of Abiraterone can be decreased when it is combined with Lumacaftor.
AcebutololThe serum concentration of Acebutolol can be decreased when it is combined with Lumacaftor.
AceclofenacThe serum concentration of Aceclofenac can be decreased when it is combined with Lumacaftor.
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Lumacaftor.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Lumacaftor.
Acetyl sulfisoxazoleThe serum concentration of Acetyl sulfisoxazole can be decreased when it is combined with Lumacaftor.
Food Interactions
No interactions found.

References

General References
  1. Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D: 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. Lancet Respir Med. 2014 Jul;2(7):527-38. doi: 10.1016/S2213-2600(14)70132-8. Epub 2014 Jun 24. [PubMed:24973281]
  2. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]
  3. Saint-Criq V, Gray MA: Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017 Jan;74(1):93-115. doi: 10.1007/s00018-016-2391-y. Epub 2016 Oct 6. [PubMed:27714410]
  4. Kunzelmann K, Mall M: Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics. Am J Respir Med. 2003;2(4):299-309. [PubMed:14719996]
  5. Fraser-Pitt D, O'Neil D: Cystic fibrosis - a multiorgan protein misfolding disease. Future Sci OA. 2015 Sep 1;1(2):FSO57. doi: 10.4155/fso.15.57. eCollection 2015 Sep. [PubMed:28031875]
  6. MacDonald KD, McKenzie KR, Zeitlin PL: Cystic fibrosis transmembrane regulator protein mutations: 'class' opportunity for novel drug innovation. Paediatr Drugs. 2007;9(1):1-10. [PubMed:17291132]
  7. Yu H, Burton B, Huang CJ, Worley J, Cao D, Johnson JP Jr, Urrutia A, Joubran J, Seepersaud S, Sussky K, Hoffman BJ, Van Goor F: Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012 May;11(3):237-45. doi: 10.1016/j.jcf.2011.12.005. Epub 2012 Jan 30. [PubMed:22293084]
  8. Mayer M: Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the 'breakthrough'. Evid Based Med. 2016 Jun;21(3):83-6. doi: 10.1136/ebmed-2015-110325. Epub 2015 Dec 30. [PubMed:26718821]
  9. The Canadian Drug Expert Committee (CDEC): Lumacaftor/Ivacaftor Recommendation [Link]
External Links
KEGG Drug
D10134
PubChem Compound
16678941
PubChem Substance
310265173
ChemSpider
17611836
ChEBI
90951
ChEMBL
CHEMBL2103870
PharmGKB
PA166114483
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lumacaftor
ATC Codes
R07AX30 — Ivacaftor and lumacaftor
FDA label
Download (335 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
1CompletedNot AvailableCystic Fibrosis (CF)1
1CompletedTreatmentCystic Fibrosis (CF)4
2CompletedTreatmentCystic Fibrosis (CF)4
2Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
2RecruitingTreatmentCystic Fibrosis (CF)1
3Active Not RecruitingTreatmentCystic Fibrosis (CF)2
3CompletedTreatmentAdvanced Lung Disease / Cystic Fibrosis (CF)1
3CompletedTreatmentCystic Fibrosis (CF)3
3CompletedTreatmentCystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation1
3Not Yet RecruitingTreatmentCystic Fibrosis (CF)1
4CompletedOtherCystic Fibrosis (CF)1
4TerminatedTreatmentCystic Fibrosis (CF)1
Not AvailableActive Not RecruitingNot AvailableCystic Fibrosis (CF)1
Not AvailableRecruitingNot AvailableCystic Fibrosis (CF)1
Not AvailableTerminatedScreeningCystic Fibrosis (CF) / Diabetes Mellitus (DM)1
Not AvailableWithdrawnScreeningCystic Fibrosis (CF) / Diabetes Mellitus (DM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8324242No2007-04-182027-04-18Us
US8754224No2006-12-282026-12-28Us
US8410274No2006-12-282026-12-28Us
US7495103No2007-05-202027-05-20Us
US8741933No2006-11-082026-11-08Us
US8716338No2006-11-082026-11-08Us
US8846718No2008-12-042028-12-04Us
US8653103No2008-12-042028-12-04Us
US9216969No2006-11-082026-11-08Us
US8507534No2010-09-202030-09-20Us
US8993600No2010-12-112030-12-11Us
US9670163No2006-12-282026-12-28Us
US9192606No2009-09-292029-09-29Us
US7973038No2006-11-082026-11-08Us
US9150552No2008-12-042028-12-04Us
US9931334No2006-12-282026-12-28Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00376 mg/mLALOGPS
logP4.37ALOGPS
logP5.77ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)4.17ChemAxon
pKa (Strongest Basic)3.5ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area97.75 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity111.97 m3·mol-1ChemAxon
Polarizability44.12 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpyridines. These are polycyclic aromatic compounds containing a benzene ring linked to a pyridine ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Phenylpyridines
Direct Parent
Phenylpyridines
Alternative Parents
Benzodioxoles / Benzoic acids / Benzoyl derivatives / N-arylamides / Methylpyridines / Imidolactams / Cyclopropanecarboxylic acids and derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds
show 9 more
Substituents
2-phenylpyridine / Benzodioxole / Benzoic acid or derivatives / Benzoic acid / Benzoyl / N-arylamide / Methylpyridine / Cyclopropanecarboxylic acid or derivatives / Monocyclic benzene moiety / Benzenoid
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Modulator
General Function
Pdz domain binding
Specific Function
Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO...
Gene Name
CFTR
Uniprot ID
P13569
Uniprot Name
Cystic fibrosis transmembrane conductance regulator
Molecular Weight
168139.895 Da
References
  1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Jordan CL, Noah TL, Henry MM: Therapeutic challenges posed by critical drug-drug interactions in cystic fibrosis. Pediatr Pulmonol. 2016 Oct;51(S44):S61-S70. doi: 10.1002/ppul.23505. [PubMed:27662106]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]
  2. Lumacaftor/Ivacaftor FDA Label [File]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
Curator comments
Data supporting CYP2C19 induction by this drug is limited to in vitro studies.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Kuk K, Taylor-Cousar JL: Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015 Dec;9(6):313-26. doi: 10.1177/1753465815601934. Epub 2015 Sep 28. [PubMed:26416827]
  2. Lumacaftor FDA label [File]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Carrier
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
Inducer
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 29, 2015 09:12 / Updated on September 18, 2018 10:32