Identification
- Summary
Lotilaner is an antiparasitic agent used to treat Demodex blepharitis.
- Brand Names
- Xdemvy
- Generic Name
- Lotilaner
- DrugBank Accession Number
- DB17992
- Background
Lotilaner is an ectoparasiticide that is a member of the isoxazoline family of compounds.4 Lotilaner has largely been used for veterinary uses as an antiparasitic agent to treat flea and tick infestations in animals.3,6 Lotilaner consists of two enantiomers: the S-enantiomer is active in vivo, while the R-enantiomer is reported to exhibit low biological activity. The active ingredient found in drug products of lotilaner is the S-enantiomer.2
On July 25, 2023, lotilaner was approved by the FDA for the treatment of Demodex blepharitis, making it the first and only approved therapeutic for this condition.5
- Type
- Small Molecule
- Groups
- Approved, Vet approved
- Structure
Structure for Lotilaner (DB17992)
- Weight
- Average: 596.75
Monoisotopic: 594.9725646 - Chemical Formula
- C20H14Cl3F6N3O3S
- Synonyms
- 2-thiophenecarboxamide, 5-((5s)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-n-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-
- 3-methyi-n-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-((55)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)thiophene-2-carboxamide
- Credelio
- Lotilaner (ema epar: veterinary)
- External IDs
- TP 03
- TP-03
- TP03
Pharmacology
- Indication
Lotilaner is indicated for the treatment of Demodex blepharitis.4
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Demodex blepharitis •••••••••••• - Contraindications & Blackbox Warnings
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Lotilaner is a parasiticide that works against Demodex mites that cause Demodex blepharitis.4 It is also active against insects, ticks, and lice.2,3 Its activity is arthropod-specific, as it does not bind to the same therapeutic target in mammals.2
- Mechanism of action
Lotilaner is a non-competitive antagonist of the gamma-aminobutyric acid (GABA)-gated chloride channel (GABACl) selective for mites. Inhibition of GABACl causes a paralytic action in the target organism, leading to death. Lotilaner is not an inhibitor of mammalian GABA-mediated chloride channels when tested at up to 30 µM (18 µg/mL) in vitro, which is approximately 1100 times the recommended human ophthalmic dose.4
The target site in GABACl is hypothesized to be localized in a pore between the T9’ to S15’ region, an interstitial subunit region. A study suggested that lotilaner may migrate within the pore of the GABACl to its final location to stabilize the channel in a closed state; however, this hypothesis requires further investigation.2
Target Actions Organism UGaba-gated chloride channel, putative antagonistPediculus humanus subsp. corporis - Absorption
Tmax is about two hours after a single ocular administration on Day 1 and one hour after the last drug administration on Day 42. In healthy subjects, the peak concentration (Cmax) in whole blood increased after 42 days of repeated ocular administration, from 0.596 to 17.8 ng/mL. The total exposure (AUC0-12) also increased from 5.75 to 149 hr x ng/mL.4
In patients with Demodex blepharitis who received lotilaner twice daily for 42 days, the mean systemic exposure at the end of treatment was 12.0 ng/mL, with a range of 0.4-46.1 ng/mL.4
- Volume of distribution
No information is available.
- Protein binding
Lotilaner plasma protein binding is high (> 99.9%) in human plasma. The partitioning of lotilaner to human blood cells is approximately 10% (range 0-20%).4
- Metabolism
In cats, mininal metabolism of lotilaner was observed.1 Lotilaner is not metabolized by CYP enzymes.4
- Route of elimination
No information is available.
- Half-life
The effective half-life in healthy subjects, which is based on the accumulation ratio over the dosing interval of 12 hours, is 264 hours (11 days).4
- Clearance
No information is available.
- Adverse Effects
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There is no information available regarding the overdosage and acute toxicity of lotilaner.
- 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.Not Available
- Food Interactions
- No interactions found.
Products
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Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Xdemvy Solution / drops 2.5 mg/1mL Ophthalmic Tarsus Pharmaceuticals, Inc. 2023-08-14 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Microbes (bacteria, parasites)
Chemical Identifiers
- UNII
- HEH4938D7K
- CAS number
- 1369852-71-0
- InChI Key
- HDKWFBCPLKNOCK-SFHVURJKSA-N
- InChI
- InChI=1S/C20H14Cl3F6N3O3S/c1-8-2-13(36-16(8)17(34)30-6-14(33)31-7-19(24,25)26)12-5-18(35-32-12,20(27,28)29)9-3-10(21)15(23)11(22)4-9/h2-4H,5-7H2,1H3,(H,30,34)(H,31,33)/t18-/m1/s1
- IUPAC Name
- 2-({3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]thiophen-2-yl}formamido)-N-(2,2,2-trifluoroethyl)acetamide
- SMILES
- CC1=C(SC(=C1)C1=NO[C@@](C1)(C1=CC(Cl)=C(Cl)C(Cl)=C1)C(F)(F)F)C(=O)NCC(=O)NCC(F)(F)F
References
- General References
- Toutain CE, Seewald W, Jung M: Pharmacokinetics of lotilaner following a single oral or intravenous administration in cats. Parasit Vectors. 2018 Jul 13;11(1):412. doi: 10.1186/s13071-018-2966-6. [Article]
- Rufener L, Danelli V, Bertrand D, Sager H: The novel isoxazoline ectoparasiticide lotilaner (Credelio): a non-competitive antagonist specific to invertebrates gamma-aminobutyric acid-gated chloride channels (GABACls). Parasit Vectors. 2017 Nov 1;10(1):530. doi: 10.1186/s13071-017-2470-4. [Article]
- Lamassiaude N, Toubate B, Neveu C, Charnet P, Dupuy C, Debierre-Grockiego F, Dimier-Poisson I, Charvet CL: The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis. PLoS Pathog. 2021 Feb 18;17(2):e1008863. doi: 10.1371/journal.ppat.1008863. eCollection 2021 Feb. [Article]
- FDA Approved Drug Products: XDEMVY (lotilaner) 0.25%, Ophthalmic Solution (July 2023) [Link]
- Business Wire: FDA Approves XDEMVY™ (lotilaner ophthalmic solution) 0.25% for the treatment of Demodex blepharitis [Link]
- EMA Medicines Overview: Credelio [Link]
- External Links
- ChemSpider
- 32699771
- 1998841
- ChEMBL
- CHEMBL3707310
- ZINC
- ZINC000141368345
- Wikipedia
- Lotilaner
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Demodex Blepharitis 1 3 Active Not Recruiting Treatment Blepharitis 1 3 Completed Treatment Blepharitis 1 2 Active Not Recruiting Other Healthy Volunteers (HV) 1 2 Active Not Recruiting Treatment Blepharitis / Demodectic Blepharitis / Demodex Infestation of Eyelid / Meibomian Gland Dysfunction (Disorder) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution / drops Ophthalmic 2.5 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11690827 No 2018-12-14 2038-12-14 US US11690826 No 2018-12-14 2038-12-14 US US11197847 No 2021-12-14 2038-12-14 US US10835517 No 2020-11-17 2038-12-14 US US8383659 No 2013-02-26 2030-01-17 US US11752137 No 2018-12-14 2038-12-14 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source logP 5.81 Chemaxon pKa (Strongest Acidic) 11.15 Chemaxon pKa (Strongest Basic) 0.94 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 79.79 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 120.89 m3·mol-1 Chemaxon Polarizability 49.71 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Pediculus humanus subsp. corporis
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Note: The above was chosen as a representative target protein in a representative arthropod, and does not encompass all proteins affected by this agent.
- General Function
- Not Available
- Specific Function
- Chloride channel activity
- Gene Name
- 8239847
- Uniprot ID
- E0W492
- Uniprot Name
- Gaba-gated chloride channel, putative
- Molecular Weight
- 48851.68 Da
References
- Lamassiaude N, Toubate B, Neveu C, Charnet P, Dupuy C, Debierre-Grockiego F, Dimier-Poisson I, Charvet CL: The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis. PLoS Pathog. 2021 Feb 18;17(2):e1008863. doi: 10.1371/journal.ppat.1008863. eCollection 2021 Feb. [Article]
- FDA Approved Drug Products: XDEMVY (lotilaner) 0.25%, Ophthalmic Solution (July 2023) [Link]
Drug created at July 25, 2023 16:03 / Updated at July 28, 2023 21:40