Identification

Name
Moxidectin
Accession Number
DB11431
Type
Small Molecule
Groups
Investigational, Vet approved
Description

Moxidectin is a potent, broad-spectrum endectocide (antiparasitic that is active against endo- and ecto-parasites) with activity against nematodes, insects, and acari. It was first used in cattle followed by an approved use in general animals. It is a semi-synthetic methoxine derivative of nemadectin which is a 16-member pentacyclic lactone of the milbemycin class. Moxidectin differs by the absence of a disaccharide moiety on carbon 13, a substituted olefinic side chain at carbon 25 and a unique methoxime moiety at carbon 23. Due to these modifications, moxidectin is classified as a second generation macrocyclic lactone.[1] Moxidectin was developed by Medicines Development for Global Health and FDA approved in June 13, 2018.[7]

Structure
Thumb
Synonyms
  • Moxidectina
  • Moxidectinum
External IDs
CL 301,423 / CL-301,423 / CL-301423
Categories
UNII
NGU5H31YO9
CAS number
113507-06-5
Weight
Average: 639.83
Monoisotopic: 639.377117671
Chemical Formula
C37H53NO8
InChI Key
YZBLFMPOMVTDJY-LSGXYNIPSA-N
InChI
InChI=1S/C37H53NO8/c1-21(2)14-25(6)33-26(7)31(38-42-8)19-36(46-33)18-29-17-28(45-36)13-12-23(4)15-22(3)10-9-11-27-20-43-34-32(39)24(5)16-30(35(40)44-29)37(27,34)41/h9-12,14,16,21-22,26,28-30,32-34,39,41H,13,15,17-20H2,1-8H3/b10-9+,23-12+,25-14+,27-11+,38-31+/t22-,26-,28+,29-,30-,32+,33+,34+,36-,37+/m0/s1
IUPAC Name
(1'R,2R,4E,4'S,5S,6S,8'R,10'E,13'R,14'E,16'E,20'R,21'R,24'S)-21',24'-dihydroxy-4-(methoxyimino)-5,11',13',22'-tetramethyl-6-(4-methylpent-2-en-2-yl)-3',7',19'-trioxaspiro[oxane-2,6'-tetracyclo[15.6.1.1^{4,8}.0^{20,24}]pentacosane]-10',14',16',22'-tetraen-2'-one
SMILES
[H][C@@]12OC\C3=C/C=C/[C@H](C)C\C(C)=C\C[C@]4([H])C[C@@]([H])(C[C@]5(C\C(=N/OC)[C@H](C)[C@H](O5)C(\C)=C\C(C)C)O4)OC(=O)[C@]([H])(C=C(C)[C@H]1O)[C@@]23O

Pharmacology

Indication

Moxidectin is indicated for the treatment of river blindness, also called onchocerciasis, in patients aged 12 years and older. River blindness is caused by a parasitic worm Onchocerca volvulus and it is manifested as severe itching, disfiguring skin conditions and visual impairment caused by the worm's larvae.[8]

The transmission of Onchocerca volvulus is performed person to person by black flies that breed in fast-flowing rivers in sub-Saharan Africa, Yemen and South and Central America. The larvae released by the adult parasite invade skin and eyes where they can produce the severe disease manifestations.[8]

Pharmacodynamics

Moxidectin has been reported to be highly effective against Onchocerca volvulus when compared to ivermectin.[3] When moxidectin was administered in infected individuals, the microfilarial load in the skin was lower even when compared to the current therapy, ivermectin. The levels of microfilarial got reduced to an undetectable level while being safe to be used in mass drug administration.[9]

Mechanism of action

Moxidectin selectively binds to the parasite's GABA-A and glutamate-gated chloride ion channels which are vital for the function of invertebrate nerve and muscle cells. It presents activity against the parasite but it does not kill him.[8] Once moxidectin is bound, there is an increased permeability leading to an influx of chloride ions and flaccid paralysis of the parasite.[1]

TargetActionsOrganism
AGlutamate-gated chloride channel
binder
Onchocerca volvulus
AGABAA gated chloride channel
binder
Onchocerca volvulus
NABC transporters
binder
Onchocerca volvulus
Absorption

The penetration of moxidectin in the parasite is not restricted as this compound is a very poor substrate of p-glycoprotein, which is vital for the reduction of the uptake of lipophilic compounds from the GI tract and for the increase in biliary, intestinal and renal secretion. After oral administration of moxidectin, the plasma maximal concentration of 70.4 mg/kg was reached after 0.37 day with a reported AUC of 363.6 mcg/day/ml.[1] It is also important to mention that oral bioavailability is enhanced with the co-administration with lipids.[6]

Volume of distribution

Moxidectin presents a larger volume of distribution and mean residence time when compared to ivermectin. The reported volume of distribution is of 1.2 l/kg.[3]

Protein binding

This pharmacokinetic property in humans is unknown.[Label]

Metabolism

Reports have registered enzymatic modification in humans and in nematodes. In the case of moxidectin, there has been registered C29-30- and C14-mono-hydroxymethyl derivatives mainly by the cytochrome CYP3A and CYP2B. The metabolism of moxidectin is considered to contribute to a small extent to the elimination.[3] Some other metabolites formed are O-demethyl-dihydroxy metabolites. The metabolism of the of moxidectin is not major as the major residue in fat, liver, kidney and muscle is the unchanged moxidectin.[5]

Route of elimination

When moxidectin is orally administered, 2% of the dose is eliminated unchanged in the feces within 72 hours. Renal elimination is negligible.[Label]

Half life

Moxidectin reporter terminal half-life is 20.2 days.[3]

Clearance

The apparent clearance of moxidectin is 3.5 L/hour.[4]

Toxicity

Moxidectin is reported to be safe as it is reported to be a poor substrate of P-glycoprotein.[1] The reported LD50in mice are in the range of 70-131 micromol/kg.[2] Carcinogenicity studies have not been performed. Moxidectin was shown to present no effects in genotoxicity, mutagenicity and fertility.[Label] The reports of overdose there are related to the presence of transient and self-limiting neurological signs including the presence of convulsions.[10]

Affected organisms
  • Microbes (bacteria, parasites)
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Moxidectin can be increased when it is combined with Abemaciclib.
AcetaminophenThe serum concentration of Moxidectin can be increased when it is combined with Acetaminophen.
AfatinibThe serum concentration of Moxidectin can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Moxidectin can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Moxidectin can be decreased when it is combined with Aldosterone.
AlectinibThe serum concentration of Moxidectin can be increased when it is combined with Alectinib.
AmiodaroneThe serum concentration of Moxidectin can be increased when it is combined with Amiodarone.
AmlodipineThe serum concentration of Moxidectin can be increased when it is combined with Amlodipine.
AmodiaquineThe serum concentration of Moxidectin can be increased when it is combined with Amodiaquine.
AmoxapineThe serum concentration of Moxidectin can be increased when it is combined with Amoxapine.
Food Interactions
Not Available

References

General References
  1. Cobb R, Boeckh A: Moxidectin: a review of chemistry, pharmacokinetics and use in horses. Parasit Vectors. 2009 Sep 25;2 Suppl 2:S5. doi: 10.1186/1756-3305-2-S2-S5. [PubMed:19778466]
  2. Menez C, Sutra JF, Prichard R, Lespine A: Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice and effects on mammalian GABA(A) channel activity. PLoS Negl Trop Dis. 2012;6(11):e1883. doi: 10.1371/journal.pntd.0001883. Epub 2012 Nov 1. [PubMed:23133688]
  3. Prichard R, Menez C, Lespine A: Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53. doi: 10.1016/j.ijpddr.2012.04.001. eCollection 2012 Dec. [PubMed:24533275]
  4. Korth-Bradley JM, Parks V, Chalon S, Gourley I, Matschke K, Gossart S, Bryson P, Fleckenstein L: Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women. Antimicrob Agents Chemother. 2011 Nov;55(11):5200-4. doi: 10.1128/AAC.00311-11. Epub 2011 Sep 6. [PubMed:21896908]
  5. Brittain H. (2013). Profiles of drug substances and related methodology. Volume 38 (1st ed.). Elsevier. [ISBN:978-0-12-407691-4]
  6. Varga M. (2014). Textbook of rabbit medicine (2nd ed.). Butterworth Heinmann.
  7. FDA approval [Link]
  8. Pnswire [Link]
  9. Luxembourg Institute of Health [Link]
  10. EMA reports [File]
External Links
KEGG Drug
D05084
ChemSpider
22901017
ChEMBL
CHEMBL2104415
Wikipedia
Moxidectin
FDA label
Download (131 KB)
MSDS
Download (96.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentQT Effects in Healthy Volunteers1
1CompletedNot AvailableInfection NOS2
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentOnchocerciasis1
2CompletedTreatmentTrichuris Trichiura; Infection1
2WithdrawnTreatmentOnchocerciasis1
3CompletedTreatmentOnchocerciasis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)145-154 ºC'MSDS'
boiling point (°C)When found in oily form it is expected to boil at 160 ºC'MSDS'
water solubilityInsoluble'MSDS'
logP6Menez C. et al. PLoS Negl Trop Dis. (2012)
pKa12.8Brittain H. Profiles of Drug Substances, Excipients and Related Methodology. (2013)
Predicted Properties
PropertyValueSource
Water Solubility0.0052 mg/mLALOGPS
logP5.3ALOGPS
logP5.67ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)2.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area116.04 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity179.22 m3·mol-1ChemAxon
Polarizability71.02 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
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 milbemycins. These are a group of macrolides with a structure containing a 16-membered lactone ring fused to a 1,7-dioxaspiroundecane ring system and to either a benzofuran (or hydrogenated derivative thereof). In some cases (e.g. Milbemycin E), the tetrahydrofuranyl ring is missing. Milbemycins can be o-glycosylated at C13 to form Avermectins. Milbemycins are produced by Streptomyces species.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Macrolides and analogues
Sub Class
Milbemycins
Direct Parent
Milbemycins
Alternative Parents
Ketals / Oxanes / Tetrahydrofurans / Tertiary alcohols / Secondary alcohols / Oxime ethers / Lactones / Carboxylic acid esters / Oxacyclic compounds / Monocarboxylic acids and derivatives
show 5 more
Substituents
Milbemycin / Ketal / Oxane / Tertiary alcohol / Tetrahydrofuran / Carboxylic acid ester / Lactone / Oxime ether / Secondary alcohol / Acetal
show 16 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Onchocerca volvulus
Pharmacological action
Yes
Actions
Binder
General Function
Not Available
Specific Function
Extracellular ligand-gated ion channel activity
Gene Name
GluClX
Uniprot ID
Q25634
Uniprot Name
Glutamate-gated chloride channel
Molecular Weight
40736.84 Da
References
  1. Cobb R, Boeckh A: Moxidectin: a review of chemistry, pharmacokinetics and use in horses. Parasit Vectors. 2009 Sep 25;2 Suppl 2:S5. doi: 10.1186/1756-3305-2-S2-S5. [PubMed:19778466]
  2. Pnswire [Link]
2. GABAA gated chloride channel
Kind
Protein group
Organism
Onchocerca volvulus
Pharmacological action
Yes
Actions
Binder
References
  1. Cobb R, Boeckh A: Moxidectin: a review of chemistry, pharmacokinetics and use in horses. Parasit Vectors. 2009 Sep 25;2 Suppl 2:S5. doi: 10.1186/1756-3305-2-S2-S5. [PubMed:19778466]
  2. Pnswire [Link]
3. ABC transporters
Kind
Protein group
Organism
Onchocerca volvulus
Pharmacological action
No
Actions
Binder
References
  1. Cobb R, Boeckh A: Moxidectin: a review of chemistry, pharmacokinetics and use in horses. Parasit Vectors. 2009 Sep 25;2 Suppl 2:S5. doi: 10.1186/1756-3305-2-S2-S5. [PubMed:19778466]
  2. Pnswire [Link]

Enzymes

Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
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...

Components:
References
  1. Prichard R, Menez C, Lespine A: Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53. doi: 10.1016/j.ijpddr.2012.04.001. eCollection 2012 Dec. [PubMed:24533275]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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
Not Available
Gene Name
CYP2B
Uniprot ID
Q14097
Uniprot Name
CYP2B protein
Molecular Weight
43147.81 Da
References
  1. Prichard R, Menez C, Lespine A: Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53. doi: 10.1016/j.ijpddr.2012.04.001. eCollection 2012 Dec. [PubMed:24533275]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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
References
  1. Prichard R, Menez C, Lespine A: Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53. doi: 10.1016/j.ijpddr.2012.04.001. eCollection 2012 Dec. [PubMed:24533275]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Prichard R, Menez C, Lespine A: Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53. doi: 10.1016/j.ijpddr.2012.04.001. eCollection 2012 Dec. [PubMed:24533275]

Drug created on February 25, 2016 11:44 / Updated on November 02, 2018 07:10