Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato

Kunkle, Bruce N.; Daly, Seán; Dumont, Pascal; Drag, Marlene; Larsen, Diane

doi:10.1016/j.vetpar.2014.02.018

Cited by 28 publications

(14 citation statements)

References 10 publications

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“…Similarly, a single dose of NexGard®, reduced populations of C. felis by 100% within 24 h and blocked egg production by >99% over 36 days [22, 23]; additional re-treatment at days 28–30, achieved total flea control by 60 days [24]. Other studies of single doses of NexGard® report complete elimination of pre-existing Dermacentor reticulatus, D. variabilis and Ixodes ricinus infestations and sustained efficacy of >96% one month later [25, 26] and significant reductions in R. sanguineus and Haemaphysalis longicornis by >96% after 35 days [27] and 92% after 30 days [28], respectively; maximum plasma levels are observed at 2–6 h and mean half-life is 15.5 days [17]. A direct comparison of immediate efficacy of Bravecto® and NexGard® against R. sanguineus demonstrated that onset of activity was 4 h and 8 h, respectively, and 100% mortality was achieved within 12 h and 48 h, respectively [21].…”

Section: Discussionmentioning

confidence: 99%

Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease

et al. 2017

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BackgroundDespite large-scale reductions in Chagas disease prevalence across Central and South America, Trypanosoma cruzi infection remains a considerable public health problem in the Gran Chaco region where vector-borne transmission persists. In these communities, peridomestic animals are major blood-meal sources for triatomines, and household presence of infected dogs increases T. cruzi transmission risk for humans. To address the pressing need for field-friendly, complementary methods to reduce triatomine infestation and interrupt T. cruzi transmission, this study evaluated the systemic activity of three commercial, oral, single dose insecticides Fluralaner (Bravecto®), Afoxolaner (NexGard®) and Spinosad (Comfortis®) in canine feed-through assays against Triatoma infestans, the principal domestic vector species in the Southern Cone of South America.MethodsTwelve healthy, outbred dogs were recruited from the Zoonosis Surveillance and Control Program in Santa Cruz, Bolivia, and randomized to three treatment groups, each containing one control and three treated dogs. Following oral drug administration, colony-reared second and third stage T. infestans instars were offered to feed on dogs for 30 min at 2, 7, 21, 34 and 51 days post-treatment.ResultsEighty-five per cent (768/907) of T. infestans successfully blood-fed during bioassays, with significantly higher proportions of bugs becoming fully-engorged when exposed to Bravecto® treated dogs (P < 0.001) for reasons unknown. Exposure to Bravecto® or NexGard® induced 100% triatomine mortality in fully- or semi-engorged bugs within 5 days of feeding for the entire follow-up period. The lethality effect for Comfortis® was much lower (50–70%) and declined almost entirely after 51 days. Instead Comfortis® treatment resulted in substantial morbidity; of these, 30% fully recovered whereas 53% remained morbid after 120 h, the latter subsequently unable to feed 30 days later.ConclusionsA single oral dose of Fluralaner or Afoxolaner was safe and well tolerated, producing complete triatomine mortality on treated dogs over 7.3 weeks. While both drugs were highly efficacious, more bugs exposed to Fluralaner took complete blood-meals, and experienced rapid knock-down. Coupled with its longer residual activity, Fluralaner represents an ideal insecticide for development into a complementary, operationally-feasible, community-level method of reducing triatomine infestation and potentially controlling T. cruzi transmission, in the Gran Chaco region.

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Section: Discussionmentioning

confidence: 99%

Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease

et al. 2017

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“…Afoxolaner is a highly effective ectoparasiticide used against flea and tick infestations in dogs (Dumont et al ., ,b; Hunter et al ., ; Kondo et al ., ; Kunkle et al ., ,b; Mitchell et al ., ,b). The high potency against fleas and ticks is a hallmark of isoxazoline parasiticides (Ozoe et al ., ; Woods et al ., ).…”

Section: Introductionmentioning

confidence: 99%

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

Letendre¹,

Harriman²,

Drag³

et al. 2016

Vet Pharm & Therapeutics

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The pharmacokinetics of afoxolaner and milbemycin oxime (A3 and A4 forms) in dogs were evaluated following the oral administration of NexGard Spectra (Merial), a fixed combination chewable formulation of these two active pharmaceutical ingredients. Absorption of actives was rapid at levels that provide the minimum effective doses of 2.5 mg/kg and 0.5 mg/kg of afoxolaner and milbemycin oxime, respectively. The time to maximum afoxolaner plasma concentrations (t ) was 2-4 h. The milbemycin t was 1-2 h. The terminal plasma half-life (t ) and the oral bioavailability were 14 ± 3 days and 88.3% for afoxolaner, 1.6 ± 0.4 days and 80.5% for milbemycin oxime A3 and 3.3 ± 1.4 days and 65.1% for milbemycin oxime A4. The volume of distribution (V ) and systemic clearance (Cls) were determined following an IV dose of afoxolaner or milbemycin oxime. The V was 2.6 ± 0.6, 2.7 ± 0.4 and 2.6 ± 0.6 L/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The Cls was 5.0 ± 1.2, 75 ± 22 and 41 ± 12 mL/h/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The pharmacokinetic profile for the combination of afoxolaner and milbemycin oxime supports the rapid onset and a sustained efficacy for afoxolaner against ectoparasites and the known endoparasitic activity of milbemycin oxime.

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“…Advances in research for ectoparasite control have brought a new oral therapeutic drug forward for clinical usage. NexGard ® (Merial Inc., Duluth, GA, USA; a beef‐flavored chewable for dogs) contains afoxolaner (a compound from a new structurally unique isoxazoline class), which acts as a novel and specific blocker of insect ligand‐gated chloride ion channels (Shoop et al ., ) and is thus effective against both fleas and ticks (Dumont et al ., ,b Hunter et al ., ; Kondo et al ., Kunkle et al ., ,b Mitchell et al ., ,b). Combining afoxolaner with milbemycin oxime in a beef‐flavored chewable allows owners to administer one product per month instead of several because milbemycin oxime extends the spectrum of activity to the treatment of intestinal nematodes and prevention of heartworm disease ( Dirofilaria immitis ).…”

Section: Introductionmentioning

confidence: 99%

“…(Paper received 30 April 2016; accepted for publication 23 September 2016) INTRODUCTION Advances in research for ectoparasite control have brought a new oral therapeutic drug forward for clinical usage. NexGard â (Merial Inc., Duluth, GA, USA; a beef-flavored chewable for dogs) contains afoxolaner (a compound from a new structurally unique isoxazoline class), which acts as a novel and specific blocker of insect ligand-gated chloride ion channels (Shoop et al, 2014) and is thus effective against both fleas and ticks ,b Hunter et al, 2014Kondo et al, 2014Kunkle et al, 2014a,b Mitchell et al, 2014a.…”

mentioning

confidence: 99%

Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight‐week‐old dogs

Drag¹,

Saik²,

Harriman³

et al. 2016

Vet Pharm & Therapeutics

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The safety profile of afoxolaner (an isoxazoline molecule) when combined with milbemycin oxime (a macrocyclic lactone) was evaluated according to the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1×, 3×, or 5× the maximum exposure dose in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Three doses were administered at 28-day intervals (Days 0, 28, and 56), followed by three additional doses administered with 14-day intervals (Days 84, 98, and 112). The study ended on Day 126. Treatment groups were as follows: Group 1: untreated, sham-dosed control; Group 2: afoxolaner/milbemycin oxime chews administered at a dose of at least 5 and 1 mg/kg, respectively (1×); Group 3: afoxolaner/milbemycin oxime chews administered at a dose of at least 15 and 3 mg/kg, respectively (3); and Group 4: afoxolaner/milbemycin oxime chews administered at a dose of at least 25 and 5 mg/kg, respectively (5×). All dogs were examined for general health twice a day beginning on Day -14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner and milbemycin oxime plasma concentrations, were performed throughout the study. No afoxolaner/milbemycin oxime treatment-related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically relevant or statistically significant health abnormalities related to the administration of afoxolaner/milbemycin oxime were observed. No signs of macrocyclic lactone sensitivity were observed at any time during the study. Vomiting and diarrhea were observed sporadically across all groups including the controls. Based upon the results of this study, afoxolaner/milbemycin oxime soft chewables were shown to be safe when administered repeatedly at up to 5× the maximum exposure dose in dogs as young as 8 weeks of age.

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Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato

Cited by 28 publications

References 10 publications

Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease

Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight‐week‐old dogs

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