Lumacaftor

Identification

Summary

Lumacaftor is a protein chaperone used in combination with ivacaftor for the treatment of cystic fibrosis in patients who are homozygous for the F508del mutation in the CFTR gene.

Brand Names
Orkambi
Generic Name
Lumacaftor
DrugBank Accession Number
DB09280
Background

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 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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 452.414
Monoisotopic: 452.118378014
Chemical Formula
C24H18F2N2O5
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

Pharmacology

Indication

When used in combination with the drug lumacaftor as the product Orkambi, ivacaftor is indicated for the management of CF in patients aged one year 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.11

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to manageCystic fibrosisCombination Product in combination with: Ivacaftor (DB08820)••••••••••••
Used in combination to manageCystic fibrosis (cf)Combination Product in combination with: Ivacaftor (DB08820)••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF 18 years of age and older either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days and 25 patients (homozygous or heterozygous for F508del) completed dosing with placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 compared to placebo was -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 compared to placebo was -11 mmol/L (95% CI: -18, -4).11

Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks. Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride on Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L on Day 15 and -24.8 mmol/L on Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The within-group LS mean absolute change in sweat chloride from Week 24 to Week 26 following the 2-week washout period was 21.3 mmol/L.11

Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24. The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 to Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P<0.0001).11

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label, clinical trial (Trial 7) in 46 patients with CF, aged 1 through 2 years (homozygous for F508del) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to <9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to <14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥14 kg at screening), every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 which was sustained through Week 24. The mean absolute change from baseline in sweat chloride at Week 24 was -29.1 mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 mmol/L (95% CI: 22.3, 32.3).11

There was no direct correlation between the decrease in sweat chloride levels and an improvement in lung function (ppFEV1).11

The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin), parallel, thorough QT study in 168 healthy subjects. No meaningful changes in QTc interval were observed with either lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h dose groups. A maximum decrease in mean heart rate of up to 8 beats per minute (bpm) from baseline was observed with lumacaftor/ivacaftor treatment. In Trials 1 and 2, a similar decrease in heart rate was observed in patients during the initiation of ORKAMBI (lumacaftor 400 mg/ivacaftor 250 mg q12h).11

Results from two randomized, double-blind, placebo-controlled, 24-week clinical trials of Orkambi (lumacaftor/ Ivacaftor) indicates that a lung function improvement, as demonstrated by a mean absolute change in ppFEV1 from baseline at Week 24 of 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2.11

Mechanism of action

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has a low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. In vitro studies have demonstrated that lumacaftor acts directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic responses or clinical benefits.11

TargetActionsOrganism
ACystic fibrosis transmembrane conductance regulator
modulator
Humans
Absorption

When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher than when taken in a fasting state.11

Following multiple oral dose administrations of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportionally to doses over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.11

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.11

Protein binding

Lumacaftor is extensively protein bound in the plasma (99%), and binds primarily to albumin.11

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.11

Route of elimination

Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as the unchanged parent drug).11

Half-life

The half-life of lumacaftor is approximately 26 hours in patients with cystic fibrosis.11

Clearance

The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr.11

Adverse Effects
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Toxicity

In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of lumacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively. There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor.11

There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increase (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.11

A two-year study in Sprague-Dawley rats and a 26-week study in transgenic Tg.rasH2 mice were conducted to assess the carcinogenic potential of lumacaftor. No evidence of tumorigenicity was observed in rats at lumacaftor oral doses up to 1000 mg/kg/day (approximately 5 and 13 times the MRHD on a lumacaftor AUC basis in males and females, respectively). No evidence of tumorigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Lumacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test.11

Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the MRHD on a lumacaftor AUC basis).11

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be increased when combined with Lumacaftor.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Lumacaftor.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Lumacaftor.
AbrocitinibThe serum concentration of Abrocitinib can be decreased when it is combined with Lumacaftor.
AcalabrutinibThe serum concentration of Acalabrutinib can be decreased when it is combined with Lumacaftor.
Food Interactions
  • Take with a high fat meal. A fat-containing meal or snack should be consumed just before or just after dosing for all formulations.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
OrkambiLumacaftor (100 mg/1) + Ivacaftor (125 mg/1)Tablet, film coatedOralVertex Pharmaceuticals Incorporated2016-09-28Not applicableUS flag
OrkambiLumacaftor (75 mg/1) + Ivacaftor (94 mg/1)GranuleOralVertex Pharmaceuticals Incorporated2022-09-02Not applicableUS flag
OrkambiLumacaftor (200 mg) + Ivacaftor (125 mg)Tablet, film coatedOralVertex Pharmaceuticals (Ireland) Limited2016-09-082021-11-12EU flag
ORKAMBILumacaftor (200 MG) + Ivacaftor (125 MG)Tablet, film coatedOralVertex Pharmaceuticals (Ireland) Limited2018-06-14Not applicableItaly flag
OrkambiLumacaftor (100 mg) + Ivacaftor (125 mg)TabletOralVertex Pharmaceuticals Incorporated2017-05-03Not applicableCanada flag

Categories

ATC Codes
R07AX30 — Ivacaftor and lumacaftor
Drug Categories
Chemical TaxonomyProvided by Classyfire
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 / Alkyl fluoride / Alkyl halide / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzodioxole / Benzoic acid / Benzoic acid or derivatives / Benzoyl
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
EGP8L81APK
CAS number
936727-05-8
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

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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  9. The Canadian Drug Expert Committee (CDEC): Lumacaftor/Ivacaftor Recommendation [Link]
  10. FDA Approved Drug Products: ORKAMBI (lumacaftor/ivacaftor) granules or tablets, for oral use [Link]
  11. FDA Approved Drug Products: ORKAMBI (lumacaftor and ivacaftor) tablets or granules, for oral use (September 2022) [Link]
  12. Health Canada Approved Drug Producs: ORKAMBI (Lumacaftor / Ivacaftor) tablets for oral use [Link]
Human Metabolome Database
HMDB0247669
KEGG Drug
D10134
PubChem Compound
16678941
PubChem Substance
310265173
ChemSpider
17611836
BindingDB
50289703
RxNav
1655922
ChEBI
90951
ChEMBL
CHEMBL2103870
ZINC
ZINC000064033452
PharmGKB
PA166114483
PDBe Ligand
VX8
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lumacaftor
PDB Entries
7svd / 7svr / 8eio
FDA label
Download (335 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherCystic Fibrosis (CF)1
4TerminatedTreatmentCystic Fibrosis (CF)2
3CompletedTreatmentAdvanced Lung Disease / Cystic Fibrosis (CF)1
3CompletedTreatmentCystic Fibrosis (CF)7
3CompletedTreatmentCystic Fibrosis, Homozygous for the F508del CFTR Mutation2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
GranuleOral
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8324242No2012-12-042027-04-18US flag
US8754224No2014-06-172026-12-28US flag
US8410274No2013-04-022026-12-28US flag
US7495103No2009-02-242027-05-20US flag
US8741933No2014-06-032026-11-08US flag
US8716338No2014-05-062026-11-08US flag
US8846718No2014-09-302028-12-04US flag
US8653103No2014-02-182028-12-04US flag
US9216969No2015-12-222026-11-08US flag
US8507534No2013-08-132030-09-20US flag
US8993600No2015-03-312030-12-11US flag
US9670163No2017-06-062026-12-28US flag
US9192606No2015-11-242029-09-29US flag
US7973038No2011-07-052026-11-08US flag
US9150552No2015-10-062028-12-04US flag
US9931334No2018-04-032026-12-28US flag
US10076513No2018-09-182028-12-04US flag
US10597384No2020-03-242028-12-04US flag
US10646481No2020-05-122029-08-13US flag
US11052075No2021-07-062028-12-04US flag
US11564916No2009-08-132029-08-13US flag

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/MSsplash10-0udi-0000900000-897601bf856e55b09253
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0k9i-0269700000-90e2a7148402cfa9f682
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0zg0-0000900000-7bef3af834afe87e0dda
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000b-0930800000-22c6a379fd4ffc92987c
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0pb9-0111900000-fab86360b881afa28399
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0794300000-90d059d85f7a546da5ff
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-200.87248
predicted
DeepCCS 1.0 (2019)
[M+H]+203.26805
predicted
DeepCCS 1.0 (2019)
[M+Na]+209.18056
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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. [Article]

Enzymes

Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
  2. Lumacaftor/Ivacaftor FDA Label [File]
Kind
Protein
Organism
Humans
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. [Article]
  2. Lumacaftor/Ivacaftor FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Inducer
Curator comments
Enzyme action is based on in vitro data.
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. [Article]
  2. Lumacaftor FDA label [File]
Kind
Protein
Organism
Humans
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. [Article]
  2. Lumacaftor FDA label [File]

Carriers

Kind
Protein
Organism
Humans
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
Humans
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 at October 29, 2015 15:12 / Updated at April 20, 2023 07:02