Afoxolaner

Afoxolaner (INN^[5]) 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, Frontpro
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
AHFS/Drugs.com	International Drug Names
License data	US DailyMed: Afoxolaner
Routes of administration	By mouth
ATCvet code	QP53BE01 (WHO)
Legal status
Legal status	CA: ℞-only US: ℞-only[1][2] EU: Rx-only[3] OTC (RU)[4]
Pharmacokinetic data
Bioavailability	74% (Tmax = 2–4 hours)[4]
Elimination half-life	14 hours[4]
Excretion	Bile duct (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
DrugBank	DB11369
ChemSpider	28651525
UNII	02L07H6D0U
KEGG	D10361
ChEMBL	ChEMBL2219412
CompTox Dashboard (EPA)	DTXSID50148921
ECHA InfoCard	100.267.822
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 GABA-receptors (those gated by the neurotransmitter gamma-aminobutyric acid) and other ligand-gated chloride channels. 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][6][7]

Safety

Toxicity for mammals

According to clinical studies performed prior to 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 diarrhea (dogs, 120 and 200 mg/kg bodyweight (bw)) following high oral doses. No treatment-related effects on vomiting or diarrhea 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.^[8]
• mild gastrointestinal effects (vomiting, diarrhea), 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,^[3][9]
• (in combination with milbemycin oxime): vomiting, diarrhea, 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,^[6]
• 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.^[8]

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,^[6]
• The US Food and Drug Administration FDA reports^[10] that some drugs in this class (isoxazolines), including afoxolaner, can have adverse neurologic effects on some dogs, such as muscle tremors, ataxia, and convulsions.
• Extralabel use of afoxolaner in a pet pig has been described without any adverse effects.^[11] Experimental use in commercial pigs also did not result in any adverse effects.^[12]

Selectivity in 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.^[8]

Selectivity for insect over mammalian GABA-receptors has been demonstrated for other isoxazolines.^[13] The selectivity might be explained by the number of pharmacological differences that exist between GABA-gated chloride channels of insects and vertebrates.^[14]

Legal status

The marketing authorization was granted by the European Medicines Agency in February 2014, for Nexgard,^[3][8] and in January 2015, for Nexgard Spectra.^[7][15]

Brand names

Afoxolaner is the active ingredient of the veterinary medicinal products Nexgard,^[3] Frontpro, and Nexgard Spectra (in combination with milbemycin oxime).^{[7][16][17][18]} 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.^[19]