Afoxolaner

Afoxolaner (INN)[2] is an insecticide and acaricide that belongs to the isoxazoline chemical compound group.

Afoxolaner

Clinical data
Pronunciation	/eɪˌfɒksoʊˈlænər/ ay-FOK-soh-LAN-ər
Trade names	NexGard
Other names	4-[(5RS)-5-(5-Chloro-α,α,α-trifluoro-m-tolyl)-4,5-dihydro-5-(trifluoromethyl)-1,2-oxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide
Routes of administration	By mouth (chewables)
ATCvet code	QP53BE01 (WHO)
Legal status
Legal status	US: ℞-only OTC (RU)[1]
Pharmacokinetic data
Bioavailability	74% (Tmax = 2–4 hours)[1]
Elimination half-life	14 hours[1]
Excretion	Biliary (major route)
Identifiers
IUPAC name 4-{5-[3-Chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-N-{2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide
CAS Number	1093861-60-9
PubChem CID	25154249
ChemSpider	28651525
UNII	02L07H6D0U
KEGG	D10361
ChEMBL	ChEMBL2219412
CompTox Dashboard (EPA)	DTXSID50148921
Chemical and physical data
Formula	C26H17ClF9N3O3
Molar mass	625.88 g·mol^−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES FC(F)(F)CNC(=O)CNC(=O)c1ccc(C2=NOC(C2)(c3cc(Cl)cc(c3)C(F)(F)F)C(F)(F)F)c4ccccc14
InChI InChI=1S/C26H17ClF9N3O3/c27-15-8-13(7-14(9-15)25(31,32)33)23(26(34,35)36)10-20(39-42-23)18-5-6-19(17-4-2-1-3-16(17)18)22(41)37-11-21(40)38-12-24(28,29)30/h1-9H,10-12H2,(H,37,41)(H,38,40) Key:OXDDDHGGRFRLEE-UHFFFAOYSA-N

It acts as an antagonist at ligand-gated chloride channels, in particular those gated by the neurotransmitter gamma-aminobutyric acid (GABA-receptors). Isoxazolines, among the chloride channel modulators, bind to a distinct and unique target site within the insect GABA-gated chloride channels, thereby blocking pre-and post-synaptic transfer of chloride ions across cell membranes. Prolonged afoxolaner-induced hyperexcitation results in uncontrolled activity of the central nervous system and death of insects and acarines.[3]

Marketing

Afoxolaner is the active principle of the veterinary medicinal products NexGard (alone) and Nexgard Spectra (in combination with milbemycin oxime).[4][5][6] They are indicated for the treatment and prevention of flea infestations, and the treatment and control of tick infestations in dogs and puppies (8 weeks of age and older, weighing 4 pounds (~1.8 kilograms) of body weight or greater) for one month.[7] These products are administered orally and poisons fleas once they start feeding.

The marketing authorization was granted by the European Medicines Agency in February 2014 for NexGard and January 2015 for Nexgard Spectra, after only 14[8] and 12[9] months of quality, safety and efficacy assessment performed by the Committee for Medicinal Products for Veterinary Use (CVMP).[10] Therefore, long-term effects are not known.

List of excipients

In NexGard[11] and NexGard Spectra[3]:

• Maize starch
• Soy protein fines
• Beef braised flavouring
• Povidone (E1201)
• Macrogol 400 (reputed laxatives)
• Macrogol 4000 (reputed laxatives)
• Macrogol 15 hydroxystearate (reputed laxatives)
• Glycerol (E422)
• Triglycerides, medium-chain

Additionally in NexGard Spectra:

• Citric acid monohydrate (E330)
• Butylated hydroxytoluene (E321)

Safety

Dosage

Afoxolaner is recommended to be administered at a dose of 2.7-7 mg/kg dog's bodyweight.[11]

Toxicity for mammals

According to clinical studies performed prior marketing:

• The oral toxicity profile of afoxolaner consists of a diuretic effect (rats only), effects secondary to a reduction in food consumption (rats and rabbits only) and occasional vomiting and/or diarrhoea (dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhoea were noted following oral doses of up to 31.5 mg/kg bw in the pivotal target animal safety study, nor in the EU field trial.[9]
• mild gastrointestinal effects (vomiting, diarrhoea), pruritus, lethargy, anorexia, and neurological signs (convulsions, ataxia and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports, most reported adverse reactions being self-limiting and of short duration,[11]
• (in combination with milbemycin oxime): vomiting, diarrhoea, lethargy, anorexia, and pruritus were observed in 0.2 to 1% of 10,000 animals treated and were generally self-limiting and of short duration,[3]
• In vitro studies reported that afoxolaner can bind to dopamine and norepinephrine cellular transport receptor systems and the CB1 receptor; inhibition of these catecholaminergic systems and certain types of competitive binding at CB1 receptors may mediate pharmacodynamic effects of diuresis, decreased food consumption, and decreased body weight in animals.[9]

According to post-marketing safety experience:

• (in combination with milbemycin oxime): erythema and neurological signs (convulsions, ataxia and muscle tremors) have been reported in less than 0.1% of 10,000 animals treated, including isolated reports,[3]
• The US FDA reports[12] that some drugs in this class (isoxazolines), including afoxalaner, can have adverse neurologic effects on some dogs, such as muscle tremors, ataxia, and seizures.
• Extralabel use of afoxolaner in a pet pig has been described without any adverse effects.[13] Experimental use in commercial pigs also did not result in any adverse effects.[14]

Selectivity insects over mammalians

In vivo studies (repeat-dose toxicology in laboratory animals, target animal safety, field studies) provided by MERIAL, the company that produces afoxolaner-derivative medicines, did not show evidence of neurological or behavioural effects suggestive of GABA-mediated perturbations in mammals. The Committee for Medicinal Products for Veterinary Use (CVMP) therefore concluded that binding to dog, rat or human GABA receptors is expected to be low for afoxolaner.[9]

Selectivity for insect over mammalian GABA-receptors has been demonstrated for other isoxazolines.[15] The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of insects and vertebrates.[16]

See also

• Fluralaner

References

1. "Frontline NexGard (afoxolaner) for the Treatment and Prophylaxis of Ectoparasitic Diseases in Dogs. Full Prescribing Information" (PDF) (in Russian). Sanofi Russia. Retrieved 14 November 2016.
2. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 70" (PDF). World Health Organization. pp. 276–7. Retrieved 14 November 2016.
3. "NexGard Spectra ® product information - Annex I "Summary of product characteristics"" (PDF). European Medicines Agency. Retrieved 13 November 2019.
4. Shoop WL, Hartline EJ, Gould BR, Waddell ME, McDowell RG, Kinney JB, et al. (April 2014). "Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs". Veterinary Parasitology. 201 (3–4): 179–89. doi:10.1016/j.vetpar.2014.02.020. PMID 24631502.
5. Beugnet F, deVos C, Liebenberg J, Halos L, Fourie J (25 August 2014). "Afoxolaner against fleas: immediate efficacy and resultant mortality after short exposure on dogs" (PDF). Parasite. 21: 42. doi:10.1051/parasite/2014045. PMC 4141545. PMID 25148564.
6. Beugnet F, Crafford D, de Vos C, Kok D, Larsen D, Fourie J (August 2016). "Evaluation of the efficacy of monthly oral administration of afoxolaner plus milbemycin oxime (NexGard Spectra(®), Merial) in the prevention of adult Spirocerca lupi establishment in experimentally infected dogs". Veterinary Parasitology. 226: 150–61. doi:10.1016/j.vetpar.2016.07.002. PMID 27514901.
7. "Boehringer-Ingelheim companion-animals-product NexGard (afoxolaner)". Boehringer Ingelheim International GmbH. Retrieved 13 November 2019.
8. "CVMP Assessment Report for NEXGARD SPECTRA(EMEA/V/C/003842/0000)" (PDF). European Medicines Agency. Retrieved 14 November 2019.
9. "CVMP assessment report for NexGard (EMEA/V/C/002729/0000)" (PDF). European Medicines Agency. Retrieved 14 November 2019.
10. "Committee for Medicinal Products for Veterinary Use (CVMP) - Section "Role of the CVMP"". European Medicines Agency. Retrieved 14 November 2019.
11. "NexGard® product information - Annex I "Summary of product characteristics"" (PDF). European Medicines Angency. Retrieved 14 November 2019.
12. Medicine, Center for Veterinary. "CVM Updates - Animal Drug Safety Communication: FDA Alerts Pet Owners and Veterinarians About Potential for Neurologic Adverse Events Associated with Certain Flea and Tick Products". www.fda.gov. Retrieved 2018-09-22.
13. https://www.frontiersin.org/articles/10.3389/fvets.2020.00473/abstract
14. https://pubmed.ncbi.nlm.nih.gov/29914951/
15. Casida JE (April 2015). "Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety". Chemical Research in Toxicology. 28 (4): 560–6. doi:10.1021/tx500520w. PMID 25688713.
16. Hosie AM, Aronstein K, Sattelle DB, ffrench-Constant RH (December 1997). "Molecular biology of insect neuronal GABA receptors". Trends in Neurosciences. 20 (12): 578–83. doi:10.1016/S0166-2236(97)01127-2. PMID 9416671.