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Safety of lotilaner flavoured chewable tablets (CredelioTM) after oral administration in cats.

ABSTRACT: BACKGROUND:Lotilaner is a new member of the isoxazoline class for treatment of flea and tick infestations in cats. This laboratory study with lotilaner vanilla-yeast flavoured chewable tablets (CredelioTM, Elanco) investigated the safety in healthy kittens starting at 8 weeks of age in a randomized, blinded, parallel-group design. Lotilaner tablets were given orally once a month over eight months at one, three and five times the upper level of the maximum recommended dose range (26 mg/kg). METHODS:The safety of lotilaner flavoured chewable tablets was assessed in healthy kittens when administered orally every 4 weeks for 8 months at the highest recommended dose rates, i.e. 1× (26 mg/kg) and at elevated dose rates, i.e. 3× (78 mg/kg) and 5× (130 mg/kg). Sixteen male and 16 female healthy 8-week-old kittens, with a mean body weight of 0.79 kg and 0.75 kg, respectively, were randomized to an untreated control group or lotilaner groups at dose rates of 26 mg/kg (1×), 78 mg/kg (3×), or 130 mg/kg (5×) every four weeks over eight months. The control group was sham-dosed. All animals were fed within 30 minutes prior to treatment. Safety assessment included general health observations, detailed clinical observations, complete physical/neurological examinations, including ophthalmological examinations, electrocardiographic (ECG) and clinical pathology evaluations (haematology, clinical chemistry and urinalysis), food and water consumption, body weight, pharmacokinetic blood collections, organ macroscopic and microscopic examinations. RESULTS:Systemic exposure to lotilaner was confirmed during the course of the study in all treated animals with the exception of the control group. No treatment-related effects were seen on daily clinical observations, food consumption (wet), ophthalmoscopic, physical/neurological and microscopic examinations. Statistically significant differences were recorded in some of the clinical pathology parameters, body weights, food consumption (dry), electrocardiograms, and organ weights, but none of the recorded observations was considered to be of clinical relevance. CONCLUSIONS:Lotilaner, when administered once monthly over eight months at the highest recommended dose and overdoses of three- and five-fold, to 8-week-old healthy kittens, is well tolerated.

SUBMITTER: Kuntz EA

PROVIDER: S-EPMC6044082 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Safety of lotilaner flavoured chewable tablets (Credelio<sup>TM</sup>) after oral administration in cats.

Kuntz Emmanuelle A EA Kammanadiminti Srinivas S

Parasites & vectors 20180713 1

<h4>Background</h4>Lotilaner is a new member of the isoxazoline class for treatment of flea and tick infestations in cats. This laboratory study with lotilaner vanilla-yeast flavoured chewable tablets (Credelio<sup>TM</sup>, Elanco) investigated the safety in healthy kittens starting at 8 weeks of age in a randomized, blinded, parallel-group design. Lotilaner tablets were given orally once a month over eight months at one, three and five times the upper level of the maximum recommended dose rang ...[more]

PMID: 30001745

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Project description:Lotilaner (Credelio™, Elanco) is a novel isoxazoline that provides rapid speed of flea and tick knockdown which is sustained for at least 1 month following oral administration to dogs. The safety of lotilaner flavoured chewable tablets was investigated in a randomized, blinded, parallel-group design study in healthy Beagle puppies starting at 8 weeks of age. Lotilaner was administered orally once a month over 8 months at one, three and five times the upper level of the recommended dose range (of 20 to 43 mg/kg).The objective of this study was to determine the safety of lotilaner flavoured chewable tablets in healthy dogs when administered monthly over an extended time period at the highest recommended dose rate, i.e. 1× and at elevated dose rates, i.e. 3× and 5×. Sixteen male and 16 female healthy 8-week-old puppies, weighing ~1.5 to 3.0 kg, were randomized among four groups to be untreated controls or to receive lotilaner at dose rates of 43 mg/kg (1×), 129 mg/kg (3×), or 215 mg/kg (5×) on eight occasions - every 4 weeks over 8 months. The control group was sham-dosed. Study dogs were fed within 30 min prior to treatment. Assessment of safety was based on general health observations, detailed clinical observations, complete physical/neurological examinations, including ophthalmological examinations and clinical pathology evaluations (haematology, clinical chemistry and urinalysis), food and water consumption, body weight, pharmacokinetic blood collections, macroscopic and microscopic examinations.Blood concentrations of lotilaner confirmed systemic exposure of all study dogs with the exception of the control group. Lotilaner did not induce any treatment-related effects on body weight, food consumption, opthalmoscopic, physical/neurological and electrocardiographic examinations. For clinical pathology, no changes related to treatment were noted. There were no treatment-related changes in gross examinations. After microscopic examinations, minor findings recorded in kidneys were of no toxicological relevance. Changes in the reproductive tissues were attributed to the peri-pubertal age and growth of the animals.Lotilaner was well-tolerated in healthy puppies at 8 week of age when administered once monthly on eight occasion over 8 months at the highest recommended dose and at three and five-fold overdose.

Project description:BACKGROUND:Preclinical studies have shown that the novel isoxazoline, lotilaner (Credelio™, Elanco) administered orally to dogs, produces rapid flea and tick knockdown and sustained speed of kill for at least a month post-treatment with a wide safety margin. A field study was undertaken to validate pre-clinical results. METHODS:Dogs were enrolled at 10 veterinary clinics across the United States. Qualifying households containing up to three dogs and one primary dog with at least 10 fleas were randomized 2:1 to receive lotilaner (Credelio™, Elanco) at the recommended minimum dose of 20 mg/kg, or afoxolaner (Nexgard®, Merial), administered per label, to give a minimum dose of 2.5 mg/kg. Treatments were dispensed on Days 0, 30 and 60 for administration by owners; all household dogs received the same treatment as the primary dog. Post-enrollment flea and tick counts were made on primary dogs on Days 30, 60 and 90, and all dogs were assessed for tablet palatability and safety. RESULTS:For efficacy assessments, data were used from 111 lotilaner-treated dogs and 50 afoxolaner-treated dogs; for safety, 197 and 86 dogs, respectively. Percent reductions from baseline in geometric mean flea counts for the lotilaner group were 99.3, 99.9 and 100% on Days 30, 60 and 90, respectively, and for afoxolaner 98.3, 99.8 and 99.8% (P?<?0.001, both groups, all days). On Day 90, 100% of lotilaner-treated dogs and 93% of afoxolaner-treated dogs were flea-free. Too few ticks were present to allow assessment. There were no differences in palatability between products (P?=?0.2132), with, respectively, 94% and 96% of lotilaner and afoxolaner treatments accepted when offered by hand, in an empty food bowl or with food. Both treatments were well tolerated, alleviating clinical signs of flea allergy dermatitis (FAD) in dogs affected at enrollment. CONCLUSION:A single owner-administered lotilaner treatment was greater than 99% effective in reducing mean flea counts within 30 days. Three consecutive monthly lotilaner treatments resulted in a 100% reduction in flea infestations, and a substantial reduction in signs of FAD. Lotilaner flavored tablets were readily accepted under field conditions. The absence of treatment-related adverse events confirms the safety of lotilaner in dogs.

Project description:BACKGROUND:Lotilaner is a new isoxazoline developed as an oral ectoparasiticide for cats and dogs. Its safety, rapid killing onset of action and sustained speed of fleas and ticks kill for a minimum of one month after administration, were demonstrated in a number of laboratory studies in cats. This study was performed to demonstrate the efficacy and safety of lotilaner flavored chewable tablets for cats (Credelio™, Elanco) in controlling fleas under field conditions in European countries. METHODS:Seventeen veterinary practices in France and Spain, located in high flea prevalence regions, participated in the study. Households with a maximum of three cats and two dogs were randomized 2:1 to a lotilaner (minimum dose rate 6 mg/kg) or a topical fipronil/(S)-methoprene combination (Frontline Combo® Spot-on Cats, Merial) group (administered according to label). In each household, efficacy against fleas and flea allergy dermatitis (FAD) signs were assessed in one primary cat (bearing a minimum of five fleas on Day 0) while safety was evaluated in all cats. There were 121 households included in the lotilaner and 61 in the fipronil/(S)-methoprene groups, respectively. Treatments were administered by the cats' owners on Day 0. Flea counts and FAD assessments were made on Days 0, 14, and 28. Efficacy calculations were based on geometric mean percent reductions of live flea counts versus baseline pre-treatment counts. RESULTS:Lotilaner efficacy was 97.2 and 98.1% on Days 14 and 28, respectively. Corresponding efficacy for fipronil/(S)-methoprene was 48.3 and 46.4%. Lotilaner was superior to fipronil/(S)-methoprene at all post-Day 0 assessments and over the whole study period (P < 0.0001). At every post-administration evaluation, at least 81% of lotilaner-treated cats were flea-free as opposed to 25% in the fipronil/(S)-methoprene group. Lotilaner improved or eliminated clinical signs of FAD, including pruritus. Both products were well tolerated. CONCLUSIONS:Under field conditions in Europe, lotilaner flavored chewable tablets for cats displayed an efficacy against fleas higher than 97%; clinical signs of FAD were improved or eliminated. Lotilaner tablets were safe and provided superior flea control to fipronil/(S)-methoprene.

Project description:BackgroundThere is a continuing need for novel approaches to tick infestations treatment and control in cats. Lotilaner, an isoxazoline with rapid onset of action, has proven its efficacy against ticks in laboratory studies. A study was undertaken to confirm lotilaner's efficacy and safety in client-owned cats, at the minimum dose of 6.0 mg/kg, against the most common ticks infesting cats in Europe.MethodsTwenty clinics in Germany, Hungary and Portugal participated in the study. Households with no more than three cats were randomized 2:1 to a lotilaner or fipronil group. The first household cat with at least three live, attached ticks was the primary cat. Treatments were dispensed on days 0, 28 and 56 for owner administration. Tick counts were performed on days 0, 7, 14, 21, 28, 42, 56, 70 and 84 (primary cats) and supplementary cats were assessed for safety only, on days 28, 56 and 84. Efficacy was assessed by comparing mean day 0 live attached tick counts with subsequent counts.ResultsMost frequently retrieved ticks were Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor reticulatus, with Ixodes hexagonus also present. In the lotilaner group (n = 112) efficacy (based on geometric mean tick counts) was between 98.3-100%. For fipronil (n = 57), efficacy was between 89.6-99.6%, with live attached ticks present on some cats at all time points. Mean tick counts in lotilaner-treated cats were significantly lower than in fipronil-treated cats on days 21, 28, 42 and 56 (P < 0.05). The mean percent efficacy over all post-enrolment visits was 99.6% and 96.4% (lotilaner and fipronil group, respectively), (P < 0.0001). Lotilaner was superior to fipronil for efficacy averaged over all time points (P < 0.0001) and on individual assessment days (day 14 to 70, P < 0.0394); it was non-inferior to fipronil on the other days. Owners successfully administered all treatments, and both products were well tolerated.ConclusionsCredelioTM was effective and safe for the treatment of tick infestations in client-owned cats. Efficacy lasted one month and lotilaner was superior to fipronil on most assessment days. Cure rates ranged between 94.5-100% for lotilaner and 68.4-98.2% for fipronil.

Project description:Lotilaner (Credelio™, Elanco), a novel isoxazoline, is a systemic insecticide and acaricide that is rapidly absorbed following oral administration to dogs and has a half-life of 30 days. As part of a development program, studies were undertaken to investigate lotilaner's initial and sustained efficacy and speed of kill against fleas.Four studies were conducted to evaluate the onset of lotilaner's speed of flea knockdown at the time of treatment, and to determine the sustained speed of flea kill (SOK) up to 35 days post-treatment. Each study assessed one or two specific time points (4, 6, 8 and 12 h) post-treatment and following weekly re-infestations. In each study, dogs were randomised to a lotilaner or an untreated group based on pre-administration flea counts, and before treatment were infested with adult Ctenocephalides felis. Dogs randomised to a lotilaner group received a single treatment on Day 0, at the minimum recommended dose rate of 20 mg/kg, 30 (± 5) minutes after being fed. Efficacy was calculated using geometric, and arithmetic mean flea counts in treated versus untreated groups.On Day 0, lotilaner efficacy was 89.9% at 4 h, 99.2% at 6 h, 99.9% at 8 h, and 100% at 12 h post-treatment. At each weekly assessment, lotilaner efficacy at 4 h remained at > 97%, at 8 h remained at > 99%, and at 12 h remained at 100% through Day 35. Across all studies, there were no treatment-related adverse events.Lotilaner's rapid flea knockdown immediately following treatment and sustained SOK through 35 days post-treatment offers a new solution for helping to eliminate the health risks that accompany flea infestations on dogs. The consistency of the rapid, sustained flea SOK demonstrated in these studies generates confidence that monthly use of lotilaner in dogs can be valuable in disrupting the flea life cycle in a contaminated environment, and that newly acquired fleas will die quickly, thereby reducing the discomfort of flea bites. The sustained lotilaner SOK also provides confidence that there will be no "end-of-dose" resurgence in flea burdens with the potential accompanying consequence of flares in flea-bite hypersensitivity.

Project description:Lotilaner is a new oral ectoparasiticide from the isoxazoline class developed for the treatment of flea and tick infestations in dogs. It is formulated as pure S-enantiomer in flavoured chewable tablets (Credelio™). The pharmacokinetics of lotilaner were thoroughly determined after intravenous and oral administration and under different feeding regimens in dogs.Twenty-six adult beagle dogs were enrolled in a pharmacokinetic study evaluating either intravenous or oral administration of lotilaner. Following the oral administration of 20 mg/kg, under fed or fasted conditions, or intravenous administration of 3 mg/kg, blood samples were collected up to 35 days after treatment. The effects of timing of offering food and the amount of food consumed prior or after dosing on bioavailability were assessed in a separate study in 25 adult dogs. Lotilaner blood concentrations were measured using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were calculated by non-compartmental analysis. In addition, in vivo enantiomer stability was evaluated in an analytical study.Following oral administration in fed animals, lotilaner was readily absorbed and peak blood concentrations reached within 2 hours. The terminal half-life was 30.7 days. Food enhanced the absorption, providing an oral bioavailability above 80% and reduced the inter-individual variability. Moreover, the time of feeding with respect to dosing (fed 30 min prior, fed at dosing or fed 30 min post-dosing) or the reduction of the food ration to one-third of the normal daily ration did not impact bioavailability. Following intravenous administration, lotilaner had a low clearance of 0.18 l/kg/day, large volumes of distribution Vz and Vss of 6.35 and 6.45 l/kg, respectively and a terminal half-life of 24.6 days. In addition, there was no in vivo racemization of lotilaner.The pharmacokinetic properties of lotilaner administered orally as a flavoured chewable tablet (Credelio™) were studied in detail. With a Tmax of 2 h and a terminal half-life of 30.7 days under fed conditions, lotilaner provides a rapid onset of flea and tick killing activity with consistent and sustained efficacy for at least 1 month.

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Safety of lotilaner flavoured chewable tablets (CredelioTM) after oral administration in cats.

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Safety of lotilaner flavoured chewable tablets (Credelio<sup>TM</sup>) after oral administration in cats.

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