Abametapir

Identification

Name
Abametapir
Accession Number
DB11932
Description

Abametapir is a novel pediculicidal metalloproteinase inhibitor used to treat infestations of head lice.4 The life cycle of head lice (Pediculus capitis) is approximately 30 days, seven to twelve of which are spent as eggs laid on hair shafts near the scalp.2 Topical pediculicides generally lack adequate ovicidal activity,2 including standard-of-care treatments such as permethrin, and many require a second administration 7-10 days following the first to kill newly hatched lice that resisted the initial treatment. The necessity for follow-up treatment may lead to challenges with patient adherence, and resistance to agents like permethrin and pyrethrins/piperonyl butoxide may be significant in some areas.3

Investigations into novel ovicidal treatments revealed that several metalloproteinase enzymes were critical to the egg hatching and survival of head lice, and these enzymes were therefore identified as a potential therapeutic target.1 Abemetapir is an inhibitor of these metalloproteinase enzymes, and the first topical pediculicide to take advantage of this novel target. The improved ovicidal activity (90-100% in vitro) of abemetapir allows for a single administration, in contrast to many other topical treatments, and its novel and relatively non-specific mechanism may help to curb the development of resistance to this agent.1

Abametapir was first approved for use in the United States under the brand name Xeglyze on July 27, 2020.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 184.242
Monoisotopic: 184.100048394
Chemical Formula
C12H12N2
Synonyms
  • 5,5'-Dimethyl-2,2'-bipyridine
  • 5,5'-Dimethyl-2,2'-dipyridyl
  • Abametapir
External IDs
  • BRN 0123183
  • HA 44
  • HA-44
  • HA44

Pharmacology

Indication

Abametapir is indicated, in the context of an overall lice management program, for the topical treatment of head lice infestation in patients 6 months of age and older.4

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Abametavir has been shown to inhibit all stages of embryo development in both head and body lice1 by interfering with enzymes critical to this process. It is relatively unique amongst lice treatments in that it requires only a single application, whereas many current therapies require two applications, due to its exceptional potency and unique mechanism.1,4 Its predominant metabolite, abametapir carboxyl, has a prolonged residence time in the body, with an estimated half-life of 71 ± 40 hours or longer in adults - as this metabolite has been shown to inhibit cytochrome P450 enzymes in vitro, the use of substrates of CYP3A4, CYP2B6, or CYP1A2 should be avoided for two weeks following the administration of abametapir.4

Abametapir lotion is formulated with benzyl alcohol, which has been associated with significant toxicity following unintentional systemic exposure, particularly in neonates and low birth weight infants.4 Benzyl alcohol-containing formulations should not be administered to patients <6 months of age, and should be administered to pediatric patients cautiously and under direct supervision of an adult to mitigate the risk of unintentional oral ingestion.4

Mechanism of action

There are several metalloproteinases (enzymes requiring metal co-factors to function)1 involved in the process of louse egg hatching and survival.2,4 In vitro studies have demonstrated that metal-chelating agents can inhibit the activity of these proteins,2 and may therefore be valuable pediculicidal agents.

Abametapir is a metalloproteinase inhibitor that targets louse metalloproteinases which are critical to their development and hatching.4,2

Absorption

In a pharmacokinetic trial with both adult and pediatric patients, the Cmax and AUC0-8h in the adult group were 41 ng/mL and 121 ng.h/mL and the Cmax and AUC0-8h in the pediatric group were 73 ng/mL and 264 ng.h/mL.4 In general, systemic exposure to abametapir appears to decrease with increasing age.4 The median Tmax of abemetapir is 0.57 - 1.54 hours.4

Following topical administration, benzyl alcohol was found in detectable quantities in the serum of 7 out of 39 pediatric patients. The Cmax of benzyl alcohol in these subjects ranged from 0.52 to 3.57 μg/mL.4

The predominant circulating metabolite of abemetapir (abemtapir carboxylate) is eliminated slowly from the circulation and is therefore found at higher serum concentrations than its parent drug - based on data collected for 72 hours post-administration, the ratios of serum Cmax and AUC0-72h between abametapir and abametapir carboxylate were approximately 30 and 250, respectively.4

Volume of distribution

Data regarding the volume of distribution of abametapir are not available.

Protein binding

Both abametapir and abametapir carboxyl are high protein-bound in plasma, although the specific proteins to which they bind are unclear.4 Following topical administration, abametapir is 91.3-92.3% protein-bound and abametapir carboxyl is 96.0-97.5% protein-bound.4

Metabolism

The biotransformation of abametapir is extensive and primarily mediated by CYP1A2. It is metabolized first to abametapir hydroxyl and then further to abametapir carboxyl - the latter is cleared slowly from the plasma, resulting in higher systemic concentrations than that of the parent drug.4 In vitro studies suggest that abametapir carboxyl may act as an inhibitor of CYP3A4, CYP2B6, and CYP1A2, particularly at the relatively high and prolonged concentrations observed following topical administration of abametapir.4

Hover over products below to view reaction partners

Route of elimination

The clearance and excretion of abametapir has not been examined in patients.4

Half-life

The elimination half-lives of abametapir and its metabolites have not been well-characterized, but the estimated half-life of abametapir carboxyl is 71 ± 40 hours (or longer) in adults.4

Clearance

The clearance and excretion of abametapir has not been examined in patients.4

Adverse Effects
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Toxicity

The intraperitoneal LD50 of abametapir in mice is 225 mg/kg.5 Topical formulations of abametapir contain benzyl alcohol, which has been associated with fatal reactions including "gasping syndrome" following systemic exposure in neonates and low birth weight infants. The use of benzyl alcohol-containing abametapir formulations should be avoided in patients <6 months of age due to an increased risk of unintentional systemic absorption.4 As benzyl alcohol toxicity may also occur in pediatric patients following accidental oral ingestion, the manufacturer recommends that it be administered to pediatric patients only under the direct supervision of adult.4 Symptoms of benzyl alcohol toxicity may include significant gastrointestinal and central nervous system adverse effects, with severe cases leading to respiratory depression and death.4 If toxicity is expected, patients should be advised to contact their nearest poison control center.

The minimal amount of benzyl alcohol at which toxicity might occur is unclear. Toxicity is more likely in premature infants, low birth weight infants, and those receiving high doses.4

Affected organisms
  • Pediculus humanus
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
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Abametapir.
AbirateroneThe serum concentration of Abiraterone can be increased when it is combined with Abametapir.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Abametapir.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Abametapir.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Abametapir.
AcyclovirThe serum concentration of Acyclovir can be increased when it is combined with Abametapir.
AgomelatineThe serum concentration of Agomelatine can be increased when it is combined with Abametapir.
AlbendazoleThe serum concentration of Albendazole can be increased when it is combined with Abametapir.
AlclometasoneThe serum concentration of Alclometasone can be increased when it is combined with Abametapir.
AlectinibThe metabolism of Alectinib can be decreased when combined with Abametapir.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

International/Other Brands
Xeglyze

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as bipyridines and oligopyridines. These are organic compounds containing two pyridine rings linked to each other.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Bipyridines and oligopyridines
Direct Parent
Bipyridines and oligopyridines
Alternative Parents
Methylpyridines / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Aromatic heteromonocyclic compound / Azacycle / Bipyridine / Heteroaromatic compound / Hydrocarbon derivative / Methylpyridine / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
6UO390AMFB
CAS number
1762-34-1
InChI Key
PTRATZCAGVBFIQ-UHFFFAOYSA-N
InChI
InChI=1S/C12H12N2/c1-9-3-5-11(13-7-9)12-6-4-10(2)8-14-12/h3-8H,1-2H3
IUPAC Name
5,5'-dimethyl-2,2'-bipyridine
SMILES
CC1=CC=C(N=C1)C1=CC=C(C)C=N1

References

Synthesis Reference

Ronald Harding, Lewis David Schulz, Vernon Morrison Bowles, "Pediculicidal composition." WIPO Patent WO2015107384A2, published July, 2015.

General References
  1. Bowles VM, Yoon KS, Barker SC, Tran C, Rhodes C, Clark MJ: Ovicidal Efficacy of Abametapir Against Eggs of Human Head and Body Lice (Anoplura: Pediculidae). J Med Entomol. 2017 Jan;54(1):167-172. doi: 10.1093/jme/tjw132. Epub 2016 Aug 21. [PubMed:28082644]
  2. Bowles VM, Hanegraaf S, Ahveninen T, Sidgiddi S, Allenby K, Alsop H: Effect of a New Head Lice Treatment, Abametapir Lotion, 0.74%, on Louse Eggs: A Randomized, Double-Blind Study. Glob Pediatr Health. 2019 Feb 22;6:2333794X19831295. doi: 10.1177/2333794X19831295. eCollection 2019. [PubMed:30828591]
  3. Gunning K, Kiraly B, Pippitt K: Lice and Scabies: Treatment Update. Am Fam Physician. 2019 May 15;99(10):635-642. [PubMed:31083883]
  4. FDA Approved Drug Products: Xeglyze (Abametapir) topical lotion [Link]
  5. BioVision: Abametapir SDS [Link]
  6. BusinessWire: Dr. Reddy's Laboratories received approval of XEGLYZE™ (abametapir) lotion, 0.74%, in the U.S. [Link]
PubChem Compound
15664
PubChem Substance
347828259
ChemSpider
14899
BindingDB
50401351
ChEMBL
CHEMBL2205807
ZINC
ZINC000000403335
PDBe Ligand
EI3
Wikipedia
Abametapir
PDB Entries
5arb / 5arc / 5ard

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHead Lice Infestation2
2CompletedTreatmentHead Lice Infestation3
2CompletedTreatmentLice Infestations1
1CompletedOtherLice Infestations1
1CompletedTreatmentHead Lice Infestation2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7812163No2006-10-282026-10-28US flag
US9839631No2004-07-162024-07-16US flag
US8212038No2004-07-162024-07-16US flag
US10292389No2014-12-172034-12-17US flag
US9357783No2004-07-162024-07-16US flag
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
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.98 mg/mLALOGPS
logP2.43ALOGPS
logP2.98ChemAxon
logS-2.3ALOGPS
pKa (Strongest Basic)3.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area25.78 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity56.22 m3·mol-1ChemAxon
Polarizability21.31 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-001i-3900000000-d9c20ecce65bd94f94a1
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

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: Xeglyze (Abametapir) topical lotion [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
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. FDA Approved Drug Products: Xeglyze (Abametapir) topical lotion [Link]
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
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: Xeglyze (Abametapir) topical lotion [Link]

Drug created on October 20, 2016 15:01 / Updated on August 01, 2020 07:41

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