Identification

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Name
Lifitegrast
Accession Number
DB11611
Type
Small Molecule
Groups
Approved
Description

Lifitegrast is a FDA approved drug for the treatment of keratoconjunctivitis sicca (dry eye syndrome). It is a tetrahydroisoquinoline derivative and lymphocyte function-associated antigen-1 ( LFA-1) antagonist that was discovered through the rational design process. The ophthalmic solution was approved in July, 2016 under the trade name Xiidra. It has shown to protect the corneal surface and alleviate the symptoms of dry eye syndrome with fast onset of action and well tolerated profile in both local and systemic setting 2.

Structure
Thumb
Synonyms
  • Lifitegrast
External IDs
SAR 1118 / SAR-1118 / SHP-606 / SHP606
Product Ingredients
IngredientUNIICASInChI Key
Lifitegrast sodiumQG18FLP1KP1119276-80-0BPWOKOSRORLLIN-BQAIUKQQSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
XiidraSolution / drops50 mg/1mLOphthalmicShire2016-07-11Not applicableUs
XiidraSolution5 %OphthalmicShire Pharma Canada Ulc2018-02-12Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
038E5L962W
CAS number
1025967-78-5
Weight
Average: 615.48
Monoisotopic: 614.0681277
Chemical Formula
C29H24Cl2N2O7S
InChI Key
JFOZKMSJYSPYLN-QHCPKHFHSA-N
InChI
InChI=1S/C29H24Cl2N2O7S/c1-41(38,39)20-4-2-3-16(11-20)12-23(29(36)37)32-27(34)25-22(30)13-19-15-33(9-7-21(19)26(25)31)28(35)18-6-5-17-8-10-40-24(17)14-18/h2-6,8,10-11,13-14,23H,7,9,12,15H2,1H3,(H,32,34)(H,36,37)/t23-/m0/s1
IUPAC Name
(2S)-2-{[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl]formamido}-3-(3-methanesulfonylphenyl)propanoic acid
SMILES
CS(=O)(=O)C1=CC(C[C@H](NC(=O)C2=C(Cl)C3=C(CN(CC3)C(=O)C3=CC=C4C=COC4=C3)C=C2Cl)C(O)=O)=CC=C1

Pharmacology

Indication

For the treatment of signs and symptoms of keratoconjunctivitis sicca (dry eye syndrome).

Associated Conditions
Pharmacodynamics

Lifitegrast addresses both the symptoms and the resulting ocular surface damage by interfering with ocular inflammatory cycle 2. Lifitegrast is a lymphocyte function–associated antigen-1 antagonist through direct competitive antagonism and sequentially inhibits the T-cell recruitment, activation, and proinflammatory cytokine release associated with dry eye syndrome 4.

Mechanism of action

Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell proliferation/activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines, inflammatory mediators, chemokines, TNF-α, and IL-1 in human peripheral blood mononuclear cells.

TargetActionsOrganism
AIntegrin alpha-L
antagonist
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

The mean peak plasma concentration (Cmax) of 1.70ng/mL was reached within 15 minutes of application. Quantifiable trough plasma concentrations ranged from 0.55 ng/mL to 3.74 ng/mL 6. Observations show limited systemic exposure that produces significant clinical outcomes.

Volume of distribution
Not Available
Protein binding

Human plasma protein binding of lifitegrast was approximately 99%, independent of concentration (50 to 1000ng/mL). Binding to isolated human serum albumin was 95% to 98%, and 31.6% to 51.1% to human α1-acid glycoprotein 6.

Metabolism

Based on the findings of an in vitro metabolism study using fresh human hepatocytes, lifitegrast does not appear to undergo significant metabolism 6.

Route of elimination

Not possible to perform mass balance study to determine the main route of elimination 6.

Half life

Not possible to calculate plasma elimination half-life based on plasma concentrations of lifitegrast, but reported to be relatively short in rat I.V. pharmacokinetics study 5.

Clearance

Not possible to calculate clearance rate based on plasma concentrations of lifitegrast, but reported to be relatively fast in rat I.V. pharmacokinetics study 5. It is predicted that lifitegrast is cleared via nasal and subsequently gastrointestinal tract 6.

Toxicity

Some adverse effects in 5-25% of the patients include instillation site irritation, dysgeusia and reduced visual acuity. There is no evidence or reports of potential carcinogenic, mutagenic or fertility-altering effects of this drug.

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, Raychaudhuri A, Smith V, Semba CP: Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology. 2015 Dec;122(12):2423-31. doi: 10.1016/j.ophtha.2015.08.001. Epub 2015 Sep 11. [PubMed:26365210]
  2. Abidi A, Shukla P, Ahmad A: Lifitegrast: A novel drug for treatment of dry eye disease. J Pharmacol Pharmacother. 2016 Oct-Dec;7(4):194-198. doi: 10.4103/0976-500X.195920. [PubMed:28163544]
  3. Paton DM: Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease. Drugs Today (Barc). 2016 Sep;52(9):485-493. [PubMed:27883115]
  4. Holland EJ, Luchs J, Karpecki PM, Nichols KK, Jackson MA, Sall K, Tauber J, Roy M, Raychaudhuri A, Shojaei A: Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology. 2017 Jan;124(1):53-60. doi: 10.1016/j.ophtha.2016.09.025. Epub 2016 Oct 27. [PubMed:28079022]
  5. Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ, Hanan EJ, Oslob JD, Yu CH, Zhu J, Arkin MR, Evanchik MJ, Flanagan WM, Hoch U, Hyde J, Prabhu S, Silverman JA, Wright J: Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS Med Chem Lett. 2012 Jan 31;3(3):203-6. doi: 10.1021/ml2002482. eCollection 2012 Mar 8. [PubMed:24900456]
  6. FDA Clinical Pharmacology and Biopharmaceutics Review [Link]
External Links
KEGG Drug
D10374
PubChem Compound
11965427
PubChem Substance
347828006
ChemSpider
10139520
BindingDB
50386331
ChEBI
133023
ChEMBL
CHEMBL2048028
Wikipedia
Lifitegrast
ATC Codes
S01XA25 — Lifitegrast
AHFS Codes
  • 52:08.92 — Anti-inflammatory Agents, Miscellaneous
FDA label
Download (1.22 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentDiabetic Macular Edema (DME) / Pars Plana Vitrectomy1
2CompletedPreventionConjunctivitis, Seasonal Allergic1
2CompletedTreatmentEye Dryness1
3CompletedTreatmentDry Eye Syndrome (DES)1
3CompletedTreatmentDry Eye Syndrome (DES) / Eye Dryness2
3CompletedTreatmentDry Eye Syndrome (DES) / Eye Dryness / Keratoconjunctivitis Sicca1
4CompletedSupportive CareContact Lens Discomfort / Contact Lens Dryness / Contact Lenses1
4CompletedTreatmentEye Dryness1
4Not Yet RecruitingDiagnosticDry Eye Syndromes / Dry Eyes Chronic / Eye Dryness1
4WithdrawnBasic ScienceContact Lens Complication / Eye Dryness / Keratoconjunctivitis Sicca / Ocular Discomfort / Ocular inflammatory conditions1
4WithdrawnTreatmentContact Lens Dry Eye1
Not AvailableRecruitingNot AvailableEye Dryness1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionOphthalmic5 %
Solution / dropsOphthalmic50 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8927574No2015-01-062030-11-12Us
US7928122No2011-04-192024-11-05Us
US9085553No2015-07-212033-07-25Us
US9353088No2016-05-312030-10-21Us
US9216174No2015-12-222024-11-05Us
US7314938No2008-01-012025-03-10Us
US8084047No2011-12-272026-05-17Us
US8367701No2013-02-052029-04-15Us
US8168655No2012-05-012029-05-09Us
US8592450No2013-11-262026-05-17Us
US7790743No2010-09-072024-11-05Us
US7745460No2010-06-292024-11-05Us
US9447077No2016-09-202029-04-15Us
US9890141No2018-02-132030-10-21Us
US10124000No2018-11-132024-11-05Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.00571 mg/mLALOGPS
logP3.96ALOGPS
logP4.02ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)3.27ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area133.99 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity154.48 m3·mol-1ChemAxon
Polarizability59.49 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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 phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Phenylalanine and derivatives
Alternative Parents
N-acyl-alpha amino acids / Phenylpropanoic acids / Tetrahydroisoquinolines / 2-halobenzoic acids and derivatives / Amphetamines and derivatives / Benzenesulfonyl compounds / Benzofurans / Aryl chlorides / Vinylogous halides / Tertiary carboxylic acid amides
show 13 more
Substituents
Phenylalanine or derivatives / N-acyl-alpha amino acid or derivatives / N-acyl-alpha-amino acid / 3-phenylpropanoic-acid / Amphetamine or derivatives / Tetrahydroisoquinoline / 2-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / Benzofuran / Benzenesulfonyl group
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Metal ion binding
Specific Function
Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4. It is involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated ...
Gene Name
ITGAL
Uniprot ID
P20701
Uniprot Name
Integrin alpha-L
Molecular Weight
128768.495 Da
References
  1. Paton DM: Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease. Drugs Today (Barc). 2016 Sep;52(9):485-493. [PubMed:27883115]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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. FDA Clinical Pharmacology and Biopharmaceutics Review [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. FDA Clinical Pharmacology and Biopharmaceutics Review [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. FDA Clinical Pharmacology and Biopharmaceutics Review [Link]

Drug created on July 13, 2016 09:57 / Updated on July 16, 2019 04:49