Methods for controlling flea and tick infestations in mammals - Patents.com

Abstract

The active substance is orally administered to the mammal substantially every day, which ultimately increases the mammal's blood concentration of the active substance to an amount effective for controlling flea and / or tick infestation in the mammal. Oral administration is then discontinued for a period of at least one day, while the mammal's blood concentration of the active substance remains high enough to control flea and / or tick infestation. The period can be for 3 or 7 days. After the period has elapsed, administration of substantially daily doses can be resumed to continue to maintain the mammal's blood concentration of the active substance at an amount effective for controlling flea and / or tick infestation. The discontinuation of oral administration can occur several times over a month or more. Also disclosed is a method of establishing a regimen for administering an active substance to control flea and / or tick infestation in a mammal, using a dosage amount reduced from the labeling dosage amount for a corresponding period of time.

Description

[Technical field]

[0001]

[0001] The teachings of this disclosure relate generally to methods for controlling flea and tick infestations in mammals by administering an active substance in the feed. [Background technology]

[0002]

[0002] In addition to being pests, ticks and fleas pose a serious health risk to mammals, they are vectors of disease and also cause significant economic losses when they infest livestock.

[0003]

[0003] Ticks are vectors for many different pathogens in mammals. Examples of tick-borne diseases include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia microti), and rickettsiosis (Rocky Mountain spotted fever). Ticks also release toxins that can cause inflammation or paralysis in the host.

[0004]

[0004] Tick infestations on wild animals, such as deer, elk, caribou, moose, etc., can result in the spread of disease from herd to herd, or from wild animals to domestic animals (eg, cattle, cats and dogs) and humans.

[0005]

[0005] Livestock are also susceptible to infestations by various mites, such as the Rhipicephalus genus of mites, especially the species microplus (cattle tick), decoloratus and annulatus. Ticks, such as Rhipicephalus microplus, are particularly difficult to control, as they inhabit pastures where livestock graze. In addition to cattle, species of Rhipicephalus and other genera of mites infest and can be found in buffaloes, horses, donkeys, goats, sheep, deer, pigs, cats and dogs. Heavy tick burdens in mammals can reduce production and damage hides, as well as transmit diseases caused by parasitic protozoa, such as babesiosis ("bovine fever") and anaplasmosis.

[0006] In addition to livestock, ticks also spread diseases to pets and humans, such as Lyme disease, ascending paralysis, and Rocky Mountain spotted fever.

[0007] Worldwide, the most common ectoparasites of dogs and cats are the cat and dog fleas, Ctenocephalides felis felis and Ctenocephalides canis, respectively. Flea-related infestations are one of the leading causes of canine dermatological problems reported to veterinarians. Additionally, cat fleas are known to transmit tapeworms in dogs and cats and are also involved in the transmission of cat scratch disease and typhus.

[0007]

[0008] Of particular concern, the health-related risks of tick and flea infestations in pets extend to humans. [Centers for Disease Control and Prevention, Diseases on the Rise, Vital Signs, May 2018, available at https: / / www.cdc.gov / vitalsigns / vector-borne / ] Pets, such as dogs and cats, are increasingly common in households worldwide. Worldwide, approximately 471 million dogs and 373 million cats are kept as household pets. In the United States alone, pet ownership has tripled in the United States since the 1970s. Unfortunately, fleas and ticks can infest these pets. Infested pets expose their human owners to elevated disease risks. One way to control the risk to humans from fleas and ticks is to control the risk of infestation in pets.

[0008]

[0009] Currently available treatments for controlling flea and tick infestations have achieved varying degrees of success. Many treatments involve topical or environmental applications of chemicals that are applied to indoor and outdoor surfaces, as well as to the animal. Chemicals used include various carbamates, organophosphates, pyrethrins and pyrethroids, isoxazolines, certain macrocyclic lactones, insect and mite growth inhibitors (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles or fiproles. These compounds often have toxic side effects that are problematic for both the animal and the animal's owner. Furthermore, there is evidence that the use of these chemicals can be ineffective due to insecticide and acaricide resistance and treatment shortages.

[0009]

[0010] Topical treatment is a well-known method of controlling flea and tick infestation. There are numerous ways to deliver these treatments to the hair and skin of mammals, but many of these methods are ineffective and / or pose safety risks to the mammal or user during or after the dispensing operation. More specifically, because a physical connection between the applicator tip and the drug delivery device must be obtained when attaching the applicator tip, there is an inherent risk that the connection will be poor, causing some of the treatment to leak out of the device and come into physical contact with the user. For example, with larger canines, it can be difficult to operate the dispenser with one hand and hold the canine in place with the other, resulting in some, but not all, of the material spilling onto the floor or onto the person applying it instead of reaching the canine's skin. This leakage is not only wasteful and messy, but also exposes the user to an increased risk of suffering from dermatitis or other such health problems, especially if the user comes into direct contact with the drug.

[0010]

[0011] Oral treatments are also available for pets. However, to be effective, owners must administer treatments once every 30 to 90 days, for example. The long time between treatments creates compliance issues if owners forget to administer a dose. Summary of the Invention [Problem to be solved by the invention]

[0011]

[0012] Despite the availability of effective treatments, a recent study by Harris Poll found that 33% of pet owners do not routinely protect their pets from fleas and ticks at all. Another study found that, on average, pet owners purchase flea and tick prevention products for their pets only four months per year, despite being told that pets need to be treated with flea and tick prevention throughout the year. Thus, there is a continuing need for relatively safe and effective drugs for controlling flea and tick infestations in pets that owners can easily remember to use. [Means for solving the problem]

[0012]

[0013] Surprisingly, the present inventors have found that treatment with active agents, including but not limited to spinosyns and isoxazolines, can provide improved control of flea and tick infestations when administered orally in smaller, more frequent / longer lasting doses. Administration is combined with feed, as discussed below. However, it is also contemplated that the active agent may be administered alone or in a dosage form other than feed, such as a chew, tablet, liquid, gel, or other form suitable for oral administration. Advantageously, by using smaller, more frequent doses, less total active agent is required over the same period to control flea and tick infestations. For example, if 30 mg / kg of isoxazoline is required for a single administration over a 30 day (monthly) period, only 0.16-0.83 mg / kg per day, or a cumulative 5-25 mg / kg over the same 30 day period, is required, translating into smaller, more frequent doses.

[0013]

[0014] Advantageously, the total amount of active agent, e.g., isoxazoline and / or spinosyn, required for a therapeutically effective monthly dose can be reduced by 10-87.5% by converting to daily administration. However, from a practical standpoint, at least two problems arise: (1) producing a uniform supply, and (2) analytical control testing of very small amounts of active agent can be difficult to achieve. Analytical matrices from feed can be very complex and difficult to analyze. Analyses can range from parts per million to parts per billion for some required doses and feed concentrations. It is therefore possible for a person skilled in the art to choose to increase the daily dose so that the sum of the daily doses over a month is the same or even higher than the conventional monthly dose, e.g., 200% of the conventional monthly dose. This can be done to ensure uniformity when administering the dose as part of the daily feed, as well as to help increase analytical accuracy and reduce analytical variability.

[0014]

[0015] Furthermore, until the inventor's remarkable discovery, spinosyns were generally thought to be ineffective in controlling mites because administration was done monthly and the amount of spinosyn in the animal's blood decreased too quickly to control a mite infestation.

[0015]

[0016] The method and composition taught herein has the additional advantage of increasing compliance, because a smaller dose of active ingredient can be incorporated into feed.Owners are less likely to forget or neglect to administer treatment, since they will naturally follow a daily feeding regimen anyway.Therefore, the present disclosure provides a method for long-term control of mites in a safer and more effective way than that achieved by known treatment methods.All owners should remember is to feed their pets as they normally do.

[0016]

[0017] Additionally, the bioavailability of certain active agents can be improved by administering them with the feed. Thus, the present disclosure provides a method for long-term control of fleas and ticks in a safer and more effective manner than that achieved by previously known treatments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017]

[0018] The terms "active agent" and "active ingredient" are used interchangeably herein and refer to a biologically, nutritionally or pharma- ceutical active substance for controlling flea and / or tick infestation that is delivered to a mammal in a dosage form such as a tablet, capsule, liquid, gel, medicated feed, treat, chew, and the like.

[0018]

[0019] Spinosyns are one possible active agent. Spinosyns are naturally occurring fermentation products. They are macrolides produced by the culture of Saccharopolyspora spinosa. Fermentation of S. spinosa produces a number of agents, including spinosyn A and spinosyn D (also called A83543A and A8354D). Spinosyn A and spinosyn D are the two most active spinosyns as insecticides. Products based primarily on these two spinosyns are marketed under the generic name "spinosad." The primary spinosyn agent, spinosyn A, is particularly known to have an excellent human and mammalian safety and toxicity profile.

[0019]

[0020] Each spinosyn has a macrocyclic 12-membered ring that is part of a unique tetracyclic ring system to which two different sugars, the amino-sugar forosamine and the neutral sugar 2N,3N,4N-(tri-O-methyl)rhamnose, are attached. This unique structure sets the spinosyns apart from other macrocyclic compounds.

[0020]

[0021] Spinosyn A was the first spinosyn isolated and identified from fermentation broths of Saccharopolyspora spinosa. Subsequent studies of the fermentation broths revealed that S. spinosa produces many spinosyns, designated spinosyns A-J (A83543A-J). The major components are spinosyn A and spinosyn D. Further spinosyns, lettered K-W, have been identified from mutant strains of S. spinosa. The various spinosyns are characterized by differences in the substitution patterns of the amino groups of the phorosamine at selected sites in the tetracyclic ring system, and the 2N,3N,4N-(tri-O-methyl)rhamnose group.

[0021]

[0022] Boeck et al., in U.S. Pat. Nos. 5,362,634 (issued Nov. 8, 1994), 5,496,932 (issued March 5, 1996), and 5,571,901 (issued Nov. 5, 1996), describe spinosyns A through H and J (which they called A83543 factors A, B, C, D, E, F, G, H and J), and salts thereof. Mynderse et al., in U.S. Pat. No. 5,202,242 (issued April 13, 1993), describe spinosyns L through N (which they referred to as A83543 factors L, M and N), their N-demethylated derivatives, and their salts, and Turner et al., in U.S. Pat. Nos. 5,591,606 (issued January 7, 1997) and 5,631,155 (issued May 29, 1997), describe spinosyns Q through T (which they referred to as A83543 factors Q, R, S and T), their N-demethylated derivatives, and their salts. For example, spinosyns K, O, P, U, V, W and Y are described by Carl V. DeAmicis, James E. Dripps, Chris J. Hatton and Laura I. Karr in American Chemical Society Symposium Series: Phytochemicals for Pest Control, Chapter 11, "Physical and Biological Properties of Spinosyns: Novel Macrolide Pest-Control Agents from Fermentation", pp. 146-154 (1997).

[0022]

[0023] Spinosyns can react to form salts, which are also useful in the methods and formulations of the present disclosure. The salts are prepared using standard procedures for salt preparation. For example, spinosyn A can be neutralized with a suitable acid to form an acid addition salt. The acid addition salts of spinosyns are particularly useful. Representative suitable acid addition salts include salts formed by reaction with either organic or inorganic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, cholic acid, pamoic acid, mucic acid, glutamic acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, formic acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid, and the like.

[0023]

[0024] As used herein, the term "spinosyn" refers to an individual spinosyn factor (spinosyn A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y), an N-demethyl derivative of an individual spinosyn factor, a chemically modified spinosyn, such as spinetoram, a salt of any of the above, a metabolite of any of the above, a physiologically acceptable derivative thereof, or a combination thereof.

[0024]

[0025] Spinosyns also provide advantages because they are highly effective against fleas and / or ticks when used in the dosages described herein according to the methods disclosed herein, providing residual protection after treatment. Furthermore, spinosyns have no insecticidal or acaricidal cross-resistance to existing compounds. Thus, they are particularly beneficial against flea and / or tick populations in mammals that have existing levels of resistance to currently used products. Thus, spinosyns can be used in integrated pest management (IPM) programs to extend the life of commonly used products where resistance has not yet fully developed or has not yet developed.

[0025]

[0026] Isoxazolines are another possible active substance. Isoxazolines are a class of heterocyclic five-membered ring compounds that contain one atom each of oxygen and nitrogen located adjacent to each other as shown below.

[0026] [ka]

[0027]

[0027] All isoxazolines are derivatives of isoxazoles. They are structural isomers of the more common oxazolines and exist in three different isomeric forms depending on the position of the double bond.

[0028]

[0028] Derivatives of isoxazolines are known. For example, WO2007 / 105814, WO2008 / 122375, and WO2009 / 035004 disclose certain alkylene-linked amides. WO2010 / 032437 discloses that benzylamides can be transferred to the ortho position of isoxazolines. WO2007 / 075459 discloses phenylisoxazolines substituted with 5-6 heterocyclic rings, and WO2010 / 084067 and WO2010 / 025998 disclose phenylisoxazolines substituted with 10-11 fused aryl and heteroaryl rings. Chiral processes for preparing isoxazolines are disclosed in WO2011 / 104089 and WO2009 / 063910.

[0029] Many isoxazoline compounds are known, including but not limited to 4-(5-methyl-5-substituted pyrrolyl-4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 4-(5-substituted carbamoylmethyl 4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 3-(5-substituted carbamoylmethyl 5-substituted alkyl-4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; 4-(5-substituted carbamoylmethyl 4,5-dihydroisoxazol-3-yl)benzoic acid amide derivatives; yl)benzamidine derivatives;4-(5-substituted-5-substituted aryl-4,5-dihydroisoxazol-3-yl)benzoic acid amide compounds;3-(4-substituted phenyl)-4,5-dihydroisoxazole derivatives;5-substituted alkyl-3,5-bis-substituted phenyl-4,5-dihydroisoxazole derivatives;3-alkoxyphenyl-5-substituted-5-phenyl-4,5-dihydroisoxazole derivatives;3-alkoxyphenyl-5-substituted alkyl-5-substituted carbamoyl-4,5-dihydroisoxazole derivatives ;3-(4-Halophenyl)-5-substituted-5-substituted phenyl-4,5-dihydroisoxazole derivatives;3-(4-Nitrophenyl)-5-substituted-5-substituted phenyl-4,5-dihydroisoxazole derivatives;4-Hydroxyiminomethylbenzoic acid amide derivatives;4-Hydroxyiminomethyl N,N-dimethylbenzoic acid amide;4-Hydroxyiminomethylbenzoylpiperidine derivatives;4-Hydroxyiminomethyl N-bicycloalkylbenzoic acid amide derivatives;6-(Hydroxyiminomethyl)pyridine-2-carboxamide including voxamide derivatives; haloalkenylbenzene derivatives, such as substituted 3,3,3-trifluoro-2-propenylbenzene derivatives; 4-(isoxazolinyl)-benzamides, such as substituted 4-(5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzamides; 4-(isoxazolinyl)-benzothioamides, such as substituted 4-(5-(halomethyl)-5-phenyl-isoxazolin-3-yl)-benzothioamides; dihydroisoxazole compounds; and spirocyclic substituted isoxazolines.

[0030]

[0030] A particularly interesting isoxazoline for controlling flea and / or tick infestations in mammals is afoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-; or (b) 4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4 ,5-dihydroisoxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide), fluralaner (chemical name: (a) benzamide, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-; or (b) 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydro-1,2-oxazol-3-yl]-2-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}benzamide), sarolaner (chemical name: (a) ethanone, 1-[5'-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidin-3,1'(3'H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)-; or (b) 1-{5'-[(5S)-5-(3,5-dichloro 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-3'-H-spiro[azetidine-3,1'-[2]benzofuran]-1-yl}-2-(methylsulfonyl)ethanone), Lotilaner (chemical name: (a) 2-thiophenecarboxamide, 5-[(5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-;or (b) 3-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]thiophene-2-carboxamide), esafoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[(5S)-5-[3-chloro-5-(trifluoro (S)-4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-; or (b) (S)-4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)- (a) benzamide, 2-chloro-N-(1-cyanocyclopropyl)-5-[1'-methyl-3'-(1,1,2,2,2-pentafluoroethyl)-4'-(trifluoromethyl)[1,5'-bi-1H-pyrazol]-4-yl]-; or (b) 2-chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4' -(trifluoromethyl)-2'H-[1,3'-bipyrazol]-4-yl]benzamide), umifoxolaner (chemical name: (a) 1-naphthalenecarboxamide, 4-[(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-;or (b) 4-{(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide), modofuranel (chemical name: 6-fluoro-N-(2-fluoro-3-{[4-(heptafluoropropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]carbamoyl}phenyl)pyridine-3-carboxamide), and mivorilaner (chemical name: (a) 4H-cyclopenta[c]thiazolidinyl] (b) 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl-3-isoxazolyl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-; or (b) 3-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-N-[2-[(2,2-difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide;

[0031] More specifically, isoxazolines having the following structure are suitable for the methods and compositions of the present disclosure:

[0032] [ka]

[0033] Some isoxazolines can react to form salts, which are also useful in the methods and formulations of the present disclosure. The salts may be prepared using standard procedures for salt preparation. For example, suitable salts may be salts of hydrohalogenated acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, acid addition salts such as nitric acid, sulfuric acid, phosphoric acid, chloric acid, and perchloric acid, salts of sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, salts of carboxylic acids, such as valeric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, and citric acid, or salts of amino acids, such as glutamic acid and aspartic acid. Alternatively, metal salts are also suitable for the present disclosure. For example, alkali metal salts such as lithium, sodium and potassium, and alkaline earth metal salts such as calcium, barium and magnesium, or aluminium salts.

[0034] As used herein, the terms "isoxazoline" and "isoxazoline or a derivative thereof" refer to any isoxazoline, isoxazoline derivative, a salt thereof, a metabolite thereof, or a combination thereof.

[0035]

[0034] Isoxazolines also provide advantages because they are highly effective against fleas and / or ticks when administered orally in smaller, more frequent / longer lasting doses, with protection remaining after treatment. Furthermore, isoxazolines have no known insecticidal or acaricidal cross-resistance to existing compounds. Thus, they are particularly beneficial against flea and tick populations in mammals that have existing levels of resistance to currently used products. Thus, isoxazolines can be used in integrated pest management (IPM) programs to extend the life of commonly used products for which resistance has not yet fully developed or has not yet developed.

[0036] Systemic efficacy (e.g., ingestion of blood containing an active agent, e.g., spinosyn or isoxazoline, by fleas and ticks) provides a different mode of exposure compared to topically applied formulations where surface skin contact with the flea or tick is the mode of exposure. The advantages of oral systemic treatment and killing fleas and ticks by them ingesting blood compared to topical application and killing by contact are: a) reducing exposure to human applicators and objects in the living environments of children and mammals (e.g., flooring, carpets, furniture); b) there is no risk of loss due to exposure of mammals to water (lakes, streams, bathing, etc.) or loss due to friction; c) No risk of UV exposure and UV degradation; d) There is no problem of oxidation due to oil on the skin, and e) including the certainty that the entire dose is administered (compared to topical application, where some of the dose may drip, rub off, and / or remain in the dispensing tube immediately following treatment).

[0037] The formulations or feeds and methods of the present disclosure may further comprise, in combination with the main active substance, one or more other active substances having therapeutic efficacy. Such active substances include substances effective against fleas and ticks. The active substances may include, for example, spinosyns, isoxazolines, avermectins, milbemycins, insect or tick growth regulators (including chitin synthesis inhibitors, juvenile hormone analogs, and juvenile hormones), nitromethylenes, neonicotinoids, pyridines and pyrazoles or fiproles.

[0038] The method of the present disclosure is carried out by administering the active substance to the mammal in small and frequent doses. To facilitate habitual administration, administration can be carried out with daily feed, snacks, treats, chews, or other supplemental feed. Many different feeds are contemplated, so long as the manufacturing process and feed composition do not adversely affect the efficacy, stability, and safety of the active substance and, if applicable, other active substances. For example, feeds, snacks, treats, or other supplemental feeds in the broad categories of dry, semi-moist, canned retort feeds, or fresh refrigerated feeds can be adapted for use according to the present disclosure. The mammal is provided with a controlled amount of the active substance by consuming the feed product weekly, approximately weekly, or daily.

[0039] By incorporating a smaller dose of the active agent into an animal's feed, snack, treat, chew, or other supplemental feed composition and administering it at an effective frequency (most preferably daily), the blood concentration of the active agent will rise over time until it reaches an optimal steady state that can be maintained by daily or substantially daily administration. In contrast, when an active agent, such as a spinosyn or isoxazoline, is administered orally at a higher dose and less frequently, such as a single treatment of a larger dose administered once in a 30 day period with a "treat", the level of the active agent in the blood will spike at the time of administration and then drop until the next dose is administered. The less frequent administration of a larger dose means that the animal must consume more of the active agent with each dose, so that the blood level of the active agent does not fall below the level required for effective prevention before the next dose is administered. Furthermore, due to the rapid and sudden drop in blood levels of the spinosyn active agent, it has not been possible to maintain sufficient blood levels to control tick infestations using a once a month administration method. In contrast, spinosyns can be used in the methods of the present disclosure to control mites.

[0040] All ratios, percentages, and parts discussed herein are "by weight" unless otherwise specified.

[0040] The term "controlling tick infestation" refers to preventing, treating, minimizing or eliminating infestation by ticks in a mammal.

[0041]

[0041] The term "mites" refers to any member of the order Acari. The term "mites" includes egg, larval, nymphal, and adult stages of development. More specifically, the term mites includes mites of the families Ixodidae and Argasidae. More specifically, the term "mites" includes species of the genera Africaniella, Amblyomma, Anomalohimalaya, Bothriocroton, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Margaropus, Nosomma, Rhipicentor, Rhipicephalus, Antricola, Argas, Nothoaspis, Ornithodoros, and Otobius.

[0042]

[0042] The term "controlling flea infestation" refers to preventing, treating, minimizing or eliminating flea infestation in a mammal.

[0043] The term "flea" refers to any member of the order Siphonaptera. The term "flea" includes the egg, larva, pupae, and adult stages of development.

[0043]

[0044] The term "mammal" refers to any member of the class Mammalia. In particular, it can refer to wild mammals such as wolves, coyotes, jackals, deer, elk, moose, reindeer, etc. It can also refer to domestic animals such as cows, sheep, pigs, bison, cattle, etc. It can also refer to pets. It can also refer to humans.

[0044]

[0045] The term "pet" refers to any domestic animal that can be kept as a pet, including, but not limited to, horses, dogs, wolves, coyotes, cats, hamsters, gerbils, mice, guinea pigs, ferrets, rabbits, etc.

[0045]

[0046] The term "canine" refers to any member of the genus Canis, and includes species such as wolves, dogs, coyotes, and jackals.

[0047] The term "feline" refers to any member of the subfamily Felidae, and includes species such as the domestic cat, bobcat, wild cat, ocelot, members of the lynx genus, Pallas's cat, and cougar.

[0046]

[0048] In carrying out the methods of the present disclosure, a "feed" is an animal feed or treat, snack, or other supplemental feed that can be administered daily or substantially daily. By using different forms of feed, such as kibbles and treats, a pet owner can vary their canine's diet and snacks from time to time and still conveniently administer a daily dose of spinosyn.

[0047]

[0049] The term "chew" refers to a treat that has flavor and aromatic properties that are attractive to canines, but typically has no nutritional value. In carrying out the methods of the present disclosure, "feed" and / or "chew" may be used interchangeably.

[0048]

[0050] For purposes of this disclosure, the term "effective time", also referred to herein as "effective period", includes at least the period of administration necessary to achieve a level of the active agent in the blood of a mammal high enough to control fleas and / or ticks, i.e., a "therapeutically effective" level. In some embodiments, the effective time may be as little as three days. In other cases, the effective time may be seven or fifteen days or more. As discussed below, the effective time will vary depending on how frequently the active agent is administered.

[0049]

[0051] As previously alluded to, "effective time" varies depending on the frequency with which the active agent is administered. As used herein, the term "effective frequency" refers to the number of doses over a given time period that will result in a therapeutically effective concentration of the active agent in the blood of a mammal. In all cases, as used herein, "effective frequency" contemplates multiple doses of the active agent per month. Those skilled in the art will appreciate that the active agent can be administered at a wide range of frequencies. For example, the active agent can be administered every day, every other day, every third day, once a week, or even at inconsistent time intervals.

[0050]

[0052] Furthermore, as discussed above, the effective frequency may affect the period required to obtain a therapeutically effective level of the active substance in the blood of the mammal. For example, if a mammal is fed the feed composition daily, the administration period, and therefore the "effective time", required to obtain a therapeutically effective level of the active substance in the blood of the mammal will be relatively shorter than if the mammal is fed the feed composition only once or twice per week.

[0051]

[0053] Furthermore, the frequency of effectiveness is affected by the daily dose in mg / kg of mammalian body weight, especially at slightly higher daily doses where missed doses have little effect on efficacy.

[0052]

[0054] Furthermore, the frequency of effectiveness is affected by the duration of treatment: in the early stages, e.g., before the amount of active agent in the mammal's blood reaches a therapeutically effective level, the active agent may need to be administered more frequently than is required after a longer period of use, i.e., after a therapeutically effective level has been achieved.

[0053]

[0055] For the purposes of this disclosure, "substantially daily" means sufficiently regular that the concentration of the active agent in the mammal's blood rises to and remains at a therapeutically effective level. For example, the disclosed daily feed composition can preferably be fed to the mammal daily indefinitely. However, in practice, there are many reasons why days may be periodically forgotten or skipped. For example, the mammal may become unhealthy or the owner may run out of the daily medicated feed composition. The disclosed method is strong enough that even if the daily administration of the active agent is occasionally interrupted, the mammal will still be protected to some degree from fleas and / or ticks. In carrying out the method of the present disclosure, the term "substantially daily" includes at least 10 days per month, more preferably 15 days per month, and even more preferably 20 days per month. All of these feeding frequencies, whether they are, for example, three times per week, every other day, or daily, qualify as substantially daily, so long as they facilitate the active agent to reach and maintain a therapeutically effective level of the active agent in the mammal's blood.

[0054]

[0056] Surprisingly, it has been found that in some circumstances, depending on the active substance and the fleas and / or ticks whose numbers are intended to be controlled, the disclosed method is sufficiently potent that administration of the active substance can be interrupted for a period of time and yet the concentration of the active substance in the mammal's blood remains sufficiently high and control of the flea and / or tick population is maintained for the period during which supply was interrupted. For example, supply of the active substance can be interrupted for 1 day, 3 days, 7 days or for a week or more. Several illustrative examples demonstrating this are provided below. See Example 1, Example 2, Example 4, Example 7, Example 8, Example 9, Example 10 and Example 12 (demonstrating the effectiveness of the commercial label after administration of the active ingredient is interrupted). This ability to interrupt administration of the active ingredient and still maintain therapeutically effective blood concentrations exists over a wide range of dosage levels, including doses from about 10% to about 250% of the equivalent daily dose.

[0055]

[0057] Except for food animal production, administering drugs in animal food is difficult due to the problem of feed variability and the inability to maintain therapeutic drug levels over the administration period. For example, some owners feed their dogs once a day, while others feed them more than once a day. Cats often eat small meals throughout the day. Some animals may not eat for several days due to illness. For example, ivermectin is widely used in both food-producing animals and pets, but has only been used in food-producing animals by administration in feed. However, the inventors have found that building up the concentration of a specific active ingredient in the mammal's blood over time by using a smaller, substantially daily dose solves the problem of feed variability.

[0056]

[0058] Advantageously, the interruption of dose administration according to the method of the present invention has a much less adverse effect on the control of flea and tick infestation compared to the interruption of dose administration according to conventional methods, i.e., the interruption of high doses administered less frequently.Preferably, the interruption of dose administration does not occur until the blood concentration of active substance reaches a steady-state level or quasi-steady-state level high enough to control flea and / or tick infestation.However, it is also possible to interrupt daily administration / feeding after first starting the administration / feeding regimen and before the blood concentration reaches the desired amount required to control flea and / or tick population, and then resume it.In this case, it usually takes a longer time for the substantially daily administration / feeding to reach the concentration of active substance to the amount effective to control flea and / or tick population in mammals.

[0057]

[0059] The term "therapeutically effective" means that the dose or blood level of the active agent is sufficient to control flea and / or tick infestation more than if the drug was not present. The active agent may be present alone or with one or more additional active agents. Preferably, it controls flea and / or tick infestation by approximately at least 50% more than if the drug was not present, and more preferably, it controls flea and / or tick infestation by approximately at least 90% more than if the drug was not present.

[0058]

[0060] In carrying out the method of the present disclosure, an effective amount or a therapeutically effective amount of active material is orally administered to a mammal. The term "effective amount" or "therapeutically effective amount" refers to the amount required to control flea and / or tick infestation. As those skilled in the art will understand, this amount varies depending on many factors. These factors include, for example, the type of mammal being treated and its weight and overall health condition.

[0059]

[0061] Although the present disclosure describes the concentration of spinosyns in terms of feed, e.g., kibble, administration using other dosage forms, e.g., treats or chews, is also contemplated. It is also contemplated that the spinosyns may be administered alone or in a tablet, liquid, gel, or other suitable form for oral administration. One of skill in the art will appreciate that the concentration of the spinosyns will vary depending on the specific dosage form. For example, if the dosage form is a treat or chew, the concentration of the spinosyns in the treat or chew will be greater than the concentration of the spinosyns in, e.g., a kibble. For example, if the daily dose of spinosyns based on the weight of a canine is 10 mg, a typical 5 g treat or chew will contain about 0.2 percent of the spinosyns (by weight). Because the amount of kibble consumed per day is greater than 5 g, the percentage of the spinosyns in the kibble will be less.

[0060]

[0062] Generally, an effective amount of a spinosyn for controlling a flea infestation refers to a daily dose of about 0.125 to about 4.5 mg of spinosyn per kg of mammalian body weight. More generally, the effective amount is about 0.2 to about 3.75 mg per kg of mammalian body weight.

[0061]

[0063] Animal feeds for controlling flea infestations typically contain about 0.0005 to about 0.2 percent spinosyns (by weight) in the feed. Preferably, between about 0.001 and about 0.12 percent spinosyns (by weight) in the feed. Most preferably, between about 0.003 and about 0.06 percent spinosyns (by weight) in the feed.

[0062]

[0064] Generally, an effective amount of a spinosyn for controlling a tick infestation refers to a daily dose of about 0.625 to about 4.5 mg of spinosyn per kg of mammalian body weight. More generally, the effective amount is about 1 to about 3.75 mg per kg of mammalian body weight.

[0063]

[0065] Animal feeds for controlling mite infestations typically contain between about 0.005 and about 2 percent spinosyns (by weight) in the feed. Preferably, between about 0.01 and about 0.5 percent spinosyns (by weight) in the feed. Most preferably, between about 0.03 and about 0.2 percent spinosyns (by weight) in the feed.

[0064]

[0066] Isoxazolines vary in potency. Thus, the effective amount of isoxazoline must be calculated for each specific isoxazoline used in the methods of the present disclosure. In general, the effective amount of an isoxazoline as a daily dose ranges from about 12.5% ​​to 90% of the approved labeled dose for said isoxazoline divided by the length of the dosing / retreatment interval (e.g., 30 days for a monthly administered product). The specific dose selected may be sufficient to raise the mammalian blood concentration of said isoxazoline to a therapeutically effective level within about 7 days of substantially daily administration, more preferably within about 5 days of substantially daily administration, and most preferably within about 3 days of substantially daily administration.

[0065]

[0067] Although the present disclosure describes the concentration of isoxazoline in terms of feed, e.g., kibble, administration using other dosage forms, e.g., treats or chews, is also contemplated. It is also contemplated that the isoxazoline may be administered alone or in a tablet, liquid, gel, or other suitable form for oral administration. Those skilled in the art will appreciate that the concentration of isoxazoline will vary depending on the specific dosage form. For example, if the animal feed is a treat, the concentration of isoxazoline in the treat will be greater than the concentration of isoxazoline in, e.g., a kibble. For example, if the daily dose of isoxazoline based on the weight of a canine is 20 mg, a typical 5 g treat may contain about 0.004 percent isoxazoline (by weight). Since the amount of kibble consumed per day is greater than 5 g, the percentage of isoxazoline in the kibble will be less.

[0066]

[0068] For example, an effective amount of mivoliraner for controlling flea infestations may be a dose of about 0.04 to about 1.5 mg of mivoliraner per kg of mammalian body weight. More typically, the effective amount is about 0.07 to about 1.25 mg per kg of mammalian body weight.

[0067]

[0069] Animal feeds for controlling flea infestations typically contain about 0.0001 to about 0.08 percent Mivoliraner (by weight) in the feed. Preferably, between about 0.0002 and about 0.05 percent Mivoliraner (by weight) in the feed. Most preferably, between about 0.0006 and about 0.03 percent Mivoliraner component (by weight) in the feed.

[0068]

[0070] In another example, an effective amount of Lotilaner for controlling a flea infestation may be a dose of about 0.017 to about 0.6 mg of Lotilaner per kg of mammalian body weight. More typically, the effective amount is about 0.027 to about 0.5 mg per kg of mammalian body weight.

[0069]

[0071] Animal feeds for controlling flea infestations typically contain from about 0.00004 to about 0.03 percent rotilaner by weight in the feed. Preferably, there is between about 0.00008 to about 0.02 percent rotilaner by weight in the feed. Most preferably, there is between about 0.0002 to about 0.001 percent rotilaner by weight in the feed.

[0070]

[0072] In another example, an effective amount of afoxolaner for controlling a flea infestation may be a dose of about 0.002 to about 0.075 mg of afoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.003 to about 0.0625 mg of afoxolaner per kg of mammalian body weight.

[0071]

[0073] Animal feeds for controlling flea infestations typically contain about 0.000005 to about 0.03 percent afoxolaner by weight in the feed. Preferably, there is between about 0.00001 and about 0.02 percent afoxolaner by weight in the feed. Most preferably, there is between about 0.00003 and about 0.0012 percent afoxolaner by weight in the feed.

[0072]

[0074] In another example, an effective amount of sarolaner for controlling a flea infestation may be a dose of about 0.001 to about 0.036 mg of sarolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0016 to about 0.03 mg of sarolaner per kg of mammalian body weight.

[0073]

[0075] Animal feeds for controlling flea infestations typically contain about 0.000002 to about 0.03 percent sarolaner (by weight) in the feed. Preferably, between about 0.000004 and about 0.02 percent sarolaner (by weight) in the feed. Most preferably, between about 0.0003 and about 0.0006 percent sarolaner component (by weight) in the feed.

[0074]

[0076] In another example, an effective amount of fluralaner for controlling a flea infestation may be a dose of about 0.008 to about 0.3 mg of fluralaner per kg of mammalian body weight. More typically, the effective amount is about 0.013 to about 0.25 mg per kg of mammalian body weight.

[0075]

[0077] Animal feeds for controlling flea infestations typically contain about 0.00002 to about 0.03 percent fluralaner by weight in the feed. Preferably, there is between about 0.00004 and about 0.02 percent fluralaner by weight in the feed. Most preferably, there is between about 0.0001 and about 0.006 percent fluralaner by weight in the feed.

[0076]

[0078] In another example, an effective amount of umifoxolaner for controlling a flea infestation may be a dose of about 0.001 to about 0.04 mg of umifoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0017 to about 0.03125 mg per kg of mammalian body weight.

[0077]

[0079] Animal feeds for controlling flea infestations typically contain about 0.000002 to about 0.03 percent Umifoxolaner (by weight) in the feed. Preferably, between about 0.000005 and about 0.02 percent Umifoxolaner (by weight) in the feed. Most preferably, between about 0.00001 and about 0.0006 percent Umifoxolaner component (by weight) in the feed.

[0078]

[0080] In another example, an effective amount of esafoxolaner for controlling a flea infestation may be a dose of about 0.001 to about 0.038 mg of esafoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0017 to about 0.03125 mg per kg of mammalian body weight.

[0079]

[0081] Animal feeds for controlling flea infestations typically contain about 0.000002 to about 0.03 percent esafoxolaner (by weight) in the feed. Preferably, between about 0.000005 and about 0.02 percent esafoxolaner (by weight) in the feed. Most preferably, between about 0.00001 and about 0.0006 percent esafoxolaner component (by weight) in the feed.

[0080]

[0082] In another example, an effective amount of tigolaner for controlling a flea infestation may be a dose of about 0.001 to about 0.038 mg of tigolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0017 to about 0.03125 mg of tigolaner per kg of mammalian body weight.

[0081]

[0083] Animal feeds for controlling flea infestations typically contain about 0.000002 to about 0.03 percent tigolanel by weight in the feed. Preferably, between about 0.000005 and about 0.02 percent tigolanel by weight in the feed. Most preferably, between about 0.00001 and about 0.0006 percent tigolanel component by weight in the feed.

[0082]

[0084] For example, an effective amount of mivoliraner for controlling tick infestation may be a dose of about 0.21 to about 1.5 mg of mivoliraner per kg of mammalian body weight. More typically, the effective amount is about 0.33 to about 1.25 mg per kg of mammalian body weight.

[0083]

[0085] Animal feeds for controlling mite infestations typically contain about 0.001 to about 0.4 percent Mivoliraner (by weight) in the feed. Preferably, between about 0.002 and about 0.24 percent Mivoliraner (by weight) in the feed. Most preferably, between about 0.003 and about 0.12 percent Mivoliraner component (by weight) in the feed.

[0084]

[0086] In another example, an effective amount of Lotilaner for controlling a mite infestation may be a dose of about 0.083 to about 0.6 mg of Lotilaner per kg of mammalian body weight. More typically, the effective amount is about 0.133 to about 0.5 mg per kg of mammalian body weight.

[0085]

[0087] Animal feeds for controlling mite infestations typically contain from about 0.0004 to about 0.16 percent rotilaner by weight in the feed. Preferably, there is between about 0.0008 and about 0.1 percent rotilaner by weight in the feed. Most preferably, there is between about 0.002 and about 0.005 percent rotilaner by weight in the feed.

[0086]

[0088] In another example, an effective amount of afoxolaner for controlling a mite infestation may be a dose of about 0.01 to about 0.075 mg of afoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.017 to about 0.0625 mg of afoxolaner per kg of mammalian body weight.

[0087]

[0089] Animal feeds for controlling mite infestations typically contain about 0.00005 to about 0.16 percent afoxolaner by weight in the feed. Preferably, there is between about 0.0001 and about 0.1 percent afoxolaner by weight in the feed. Most preferably, there is between about 0.0003 and about 0.006 percent afoxolaner by weight in the feed.

[0088]

[0090] In another example, an effective amount of esafoxolaner for controlling a mite infestation may be a dose of about 0.005 to about 0.0375 mg of esafoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.008 to about 0.03125 mg of esafoxolaner per kg of mammalian body weight.

[0089]

[0091] Animal feeds for controlling mite infestations typically contain from about 0.00002 to about 0.16 percent esafoxolaner by weight in the feed. Preferably, between about 0.00005 and about 0.1 percent esafoxolaner by weight in the feed. Most preferably, between about 0.0001 and about 0.003 percent esafoxolaner component by weight in the feed.

[0090]

[0092] In another example, an effective amount of sarolaner for controlling a mite infestation may be a dose of about 0.005 to about 0.036 mg of sarolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0008 to about 0.03 mg of sarolaner per kg of mammalian body weight.

[0091]

[0093] Animal feeds for controlling mite infestations typically contain from about 0.00002 to about 0.16 percent sarolaner (by weight) in the feed. Preferably, between about 0.00004 and about 0.1 percent sarolaner (by weight) in the feed. Most preferably, between about 0.0001 and about 0.003 percent sarolaner component (by weight) in the feed.

[0092]

[0094] In another example, an effective amount of fluralaner for controlling tick infestation may be a dose of about 0.0417 to about 0.3 mg of fluralaner per kg of mammalian body weight. More typically, the effective amount is about 0.067 to about 0.25 mg per kg of mammalian body weight.

[0093]

[0095] Animal feeds for controlling mite infestations typically contain about 0.0002 to about 0.016 percent fluralaner by weight in the feed. Preferably, there is between about 0.0004 and about 0.1 percent fluralaner by weight in the feed. Most preferably, there is between about 0.001 and about 0.03 percent fluralaner by weight in the feed.

[0094]

[0096] In another example, an effective amount of umifoxolaner for controlling a mite infestation may be a dose of about 0.005 to about 0.375 mg of umifoxolaner per kg of mammalian body weight. More typically, the effective amount is about 0.0008 to about 0.03125 mg per kg of mammalian body weight.

[0095]

[0097] Animal feeds for controlling mite infestations typically contain between about 0.00002 and about 0.16 percent seafoxolaner by weight in the feed. Preferably, between about 0.00005 and about 0.1 percent seafoxolaner by weight in the feed. Most preferably, between about 0.0001 and about 0.003 percent seafoxolaner component by weight in the feed.

[0096]

[0098] In another example, an effective amount of tigolaner for controlling a mite infestation may be a dose of about 0.005 to about 0.0375 mg of tigolaner per kg of mammalian body weight. More typically, the effective amount is about 0.008 to about 0.03125 mg of tigolaner per kg of mammalian body weight.

[0097]

[0099] Animal feeds for controlling mite infestations typically contain from about 0.00002 to about 0.16 percent tigolanel by weight in the feed. Preferably, there is between about 0.00005 and about 0.1 percent tigolanel by weight in the feed. Most preferably, there is between about 0.0001 and about 0.003 percent tigolanel component by weight in the feed.

[0098]

[0100] In one embodiment, the present disclosure relates to a method of controlling flea and / or tick infestation in a mammal by administering a systemically active oral composition comprising an active agent and animal feed at least once per week, more preferably three times per week, and most preferably substantially daily.

[0099]

[0101] In another aspect, the disclosure relates to a systemically active oral composition comprising an active agent and an animal feed or chew.

[0102] The present disclosure also relates to the use of the active substances for the manufacture of animal feed or chews for controlling flea and / or tick infestations in mammals.

[0100]

[0103] The present disclosure also relates to a method for controlling flea and / or tick infestation in a mammal for an extended period of time, comprising administering to the mammal an effective amount of a dose of an active substance in a daily feed, orally, daily or substantially daily. A daily feed is a feed that is intended to be administered daily, but may be administered at other frequencies as described herein. The method is particularly useful for controlling fleas and / or ticks in a mammal for an extended period of time, comprising administering to the mammal an effective amount of a dose of an active substance in a daily feed, orally, substantially daily.

[0101]

[0104] An embodiment of the present disclosure is the oral administration of an amount of an active agent that is ineffective or suboptimal by itself for controlling flea and / or tick infestation in a mammal in a single dose, but that provides effective control of flea and / or tick infestation when administered repeatedly over time as described herein. By ineffective or suboptimal, we mean that a single dose and several doses result in less than a 50% reduction in flea and / or tick infestation compared to no drug administered at all, including no or substantially no reduction. This reflects the chronic rather than acute administration aspects disclosed herein.

[0102]

[0105] Embodiment 1: A method of controlling flea and / or tick infestation in a mammal in need thereof, comprising: orally administering to said mammal an effective amount of an active agent; continuing the oral administration substantially daily for several days, thereby raising the mammal's blood concentration of the active agent to an amount effective to reduce flea and / or tick infestation; The method includes discontinuing oral administration for a period of at least one day after the mammal's blood concentration of the active agent has reached an amount effective to reduce flea or tick infestation, during which period the mammal's blood concentration of the active agent remains effective to control flea and / or tick infestation.

[0103]

[0106] Embodiment 2: The method of embodiment 1, wherein the period of time is at least three consecutive days and the blood concentration of the active agent in the mammal remains effective to control a flea and / or tick infestation over the period of time.

[0104]

[0107] Embodiment 3: The method of embodiment 1, wherein the period of time is at least 7 consecutive days and the blood concentration of the active agent in the mammal remains effective to control a flea and / or tick infestation over the period of time.

[0105]

[0108] Embodiment 4: The method of any of embodiments 1-3, further comprising resuming substantially daily administration after the period of time has elapsed, thereby continuing to maintain a blood concentration of the active agent in the mammal in an amount effective to control a flea and / or tick infestation.

[0106]

[0109] Embodiment 5: The method of embodiment 4, wherein the time periods include multiple time periods, each of which is at least 1 day and all of which occur within a 30 day period.

[0110] Embodiment 6: The method of embodiment 1, wherein the active agent is selected from the group consisting of spinosyns and isoxazolines.

[0107]

[0111] Embodiment 7: The method of embodiment 6, wherein the active agent is a spinosyn.

[0112] Embodiment 8: The method of embodiment 7, wherein the spinosyn is spinosad.

[0113] Embodiment 9: The method of embodiment 6, wherein the active agent is an isoxazoline.

[0108]

[0114] Embodiment 10: The method of embodiment 9, wherein the isoxazoline is selected from the group consisting of mivolilaner, fluralaner, sarolaner, afoxolaner, lotilaner, umifoxolaner, esafoxolaner, tigolaner, modofuraner, and salts thereof.

[0109]

[0115] Embodiment 11: The method according to any one of embodiments 1 to 10, wherein the active substance is a component of a wet feed or a dry feed.

[0116] Embodiment 12: The method of embodiment 11, wherein the feed comprises dry feed.

[0110]

[0117] Embodiment 13: The method of any one of embodiments 1 to 10, wherein the active agent is a component of a chew.

[0118] Embodiment 14: A method for establishing a regimen for orally administering a reduced dose of an active agent to control flea and / or tick infestation in a mammal, comprising: (a) selecting an active agent having a predetermined dosage for oral administration to a mammal for controlling fleas and / or ticks, the predetermined dosage being for a predetermined dosing regimen of once every 30 days or once a month; (b) multiplying the predetermined dose by no more than about 0.90 to obtain a reduced dose; (c) calculating the reduced daily dose from the reduced dose; and (d) providing instructions for administering the active agent to the mammal at a reduced daily dose substantially daily over several days; whereby, after following the instructions for administration, flea and / or tick infestation in a mammal is controlled to the same or greater extent than when a predetermined dosage of active substance is administered to the mammal at intervals of once every 30 days or once a month.

[0111]

[0119] Embodiment 15: The method of embodiment 14, wherein step (b) comprises multiplying the predetermined dose by between about 0.20 and about 0.90.

[0120] Embodiment 16: The method of any one of embodiments 14 and 15, wherein step (b) comprises multiplying the predetermined dose by about 0.70 or less.

[0112]

[0121] Embodiment 17: The method of any one of embodiments 14-16, wherein step (b) comprises multiplying the predetermined dose by about 0.50 or less.

[0122] Embodiment 18: The method of any one of embodiments 14-17, wherein the active agent is selected from the group consisting of spinosyns and isoxazolines.

[0113]

[0123] Embodiment 19: The method of embodiment 18, wherein the active agent is a spinosyn.

[0124] Embodiment 20: The method of embodiment 19, wherein the spinosyn is spinosad.

[0114]

[0125] Embodiment 21: The method of embodiment 20, wherein step (b) comprises multiplying the predetermined dose by about 12.5% ​​to 90%.

[0126] Embodiment 22: The method of embodiment 20, wherein the given dosage controls fleas but not ticks, and the reduced daily dosage controls fleas and ticks.

[0115]

[0127] Embodiment 23: The method of embodiment 20, wherein carrying out steps (a)-(d) results in a maximum concentration of the active agent in the blood of the mammal that reaches less than about 10% of the maximum blood concentration reached when a predetermined dosage of the active agent is administered to the mammal at intervals of once every 30 days or once a month.

[0116]

[0128] Embodiment 24: The method of embodiment 18, wherein the active agent is an isoxazoline.

[0129] Embodiment 25: The method of embodiment 24, wherein the isoxazoline is selected from the group consisting of mivolilaner, fluralaner, sarolaner, afoxolaner, lotilaner, tigolaner, umifoxolaner, esafoxolaner, modofuraner, and salts thereof.

[0117]

[0130] Embodiment 26: The method of embodiment 25, wherein the active agent is mivolilaner.

[0131] Embodiment 27: The method of embodiment 26, wherein step (b) comprises multiplying the predetermined dose by about 0.125 to about 0.9.

[0118]

[0132] Embodiment 28: The method of embodiment 27, wherein carrying out steps (a)-(d) results in a maximum concentration of the active agent in the blood of the mammal that reaches less than about 20% of the maximum blood concentration reached when a predetermined dose of the active agent is administered to the mammal at intervals of once every 30 days or once a month.

[0119]

[0133] Embodiment 29: The method of any one of embodiments 14 to 28, wherein the active substance is an ingredient of a feed and step (d) comprises instructions for administering the feed.

[0134] Embodiment 30: The method of any of embodiments 14-28, wherein the active agent is a component of a chew and step (d) includes instructions for administering the chew.

[0120]

[0135] Embodiment 31: The method of any of embodiments 14-30, wherein step (c) comprises dividing the reduced dose by about 30 to obtain the reduced daily dose.

[0136] Embodiment 32: A feed comprising an effective amount of an active substance for controlling flea and / or tick infestation in a mammal in need thereof, Oral administration of the feed is continued substantially daily for several days, thereby increasing a blood concentration of the active agent in the mammal to an amount effective to reduce flea and / or tick infestation; After the mammal's blood concentration of the active substance has reached an amount effective to reduce flea or tick infestation, daily oral administration of the feed is discontinued for a period of at least one day, during which the mammal's blood concentration of the active substance remains effective to control flea and / or tick infestation, the feed.

[0121]

[0137] Embodiment 33: A feed according to embodiment 32, wherein the period is at least 3 consecutive days and wherein the blood concentration of the active substance in the mammal remains effective to control a flea and / or tick infestation over the period.

[0122]

[0138] Embodiment 34: A feed according to embodiment 32, wherein the period is at least 7 consecutive days and wherein the blood concentration of the active substance in the mammal remains effective to control a flea and / or tick infestation over that period.

[0123]

[0139] Embodiment 35: The feed of any of embodiments 32-34, further comprising resuming administration of the substantially daily feeding after the period of time has elapsed, thereby continuing to maintain a blood concentration of the active agent in the mammal in an amount effective to control a flea and / or tick infestation.

[0124]

[0140] Embodiment 36: The feed of embodiment 35, comprising multiple periods, each of which is at least 1 day and all occurring within a 30 day period.

[0141] Embodiment 37: A feed according to embodiment 32, wherein the active substance is selected from the group consisting of spinosyns and isoxazolines.

[0125]

[0142] Embodiment 38: A feed according to embodiment 37, wherein the active agent is a spinosyn.

[0143] Embodiment 39: The feed of embodiment 38, wherein the spinosyn is spinosad.

[0126]

[0144] Embodiment 40. A feed according to embodiment 37, wherein the active substance is an isoxazoline.

[0145] Embodiment 41: A feed according to embodiment 40, wherein the isoxazoline is selected from the group consisting of mivorilaner, fluralaner, sarolaner, afoxolaner, lotilaner, umifoxolaner, esafoxolaner, tigolaner, modofuraner, and salts thereof.

[0127]

[0146] Embodiment 42: A feed according to any one of embodiments 32 to 41, wherein the feed is a wet or dry feed or a treat.

[0147] Embodiment 43: An active substance for use in the control of flea and / or tick infestations in mammals, comprising the active agent has a predetermined dosage for oral administration to a mammal for controlling fleas and / or ticks, the predetermined dosage of the active agent being for a predetermined dosing regimen of once every 30 days or once a month, optionally repeating the predetermined dosing regimen; The given dose is multiplied by about 0.90 or less to obtain the reduced dose; The reduced dose is divided by about 30 to obtain the reduced daily dose, A reduced daily dosage of the active agent is administered to the mammal substantially daily for several days; An active substance which, after administration over a period of several days, controls the flea and / or tick population on a mammal to the same or greater extent than when a given dose of the active substance is administered to the mammal at intervals of one or more months.

[0128]

[0148] Embodiment 44: The active agent of embodiment 43, wherein the predetermined dosage amount is multiplied by between about 0.20 and about 0.90.

[0149] Embodiment 45: The active substance of any of embodiments 43 and 44, wherein the predetermined dosage amount is multiplied by about 0.70 or less.

[0129]

[0150] Embodiment 46: The active substance of any of embodiments 43 to 45, wherein the predetermined dosage amount is multiplied by about 0.50 or less.

[0151] Embodiment 47: The active agent of any one of embodiments 43 to 46, wherein the active agent is selected from the group consisting of spinosyns and isoxazolines.

[0130]

[0152] Embodiment 48: The active agent of embodiment 47, wherein the active agent is a spinosyn.

[0153] Embodiment 49: The active agent of embodiment 48, wherein the spinosyn is spinosad.

[0131]

[0154] Embodiment 50: The active substance according to embodiment 49, wherein the given dosage is multiplied by about 12.5% ​​to 90%.

[0155] Embodiment 51: An active substance according to embodiment 50, wherein the given dosage controls fleas but not mites, and wherein a reduced daily dosage controls fleas and mites.

[0132]

[0156] Embodiment 52: The active substance of embodiment 50, wherein the maximum concentration of the active substance in the blood of the mammal is reached to less than about 10% of the maximum blood concentration reached when a predetermined dose of the active substance is administered to the mammal at intervals of one month or more.

[0133]

[0157] Embodiment 53: The active agent of embodiment 47, wherein the active agent is an isoxazoline.

[0158] Embodiment 54: The active substance according to embodiment 53, wherein the isoxazoline is selected from the group consisting of mivoliraner, fluralaner, sarolaner, afoxolaner, lotilaner, tigolaner, umifoxolaner, esafoxolaner, modofuraner, and salts thereof.

[0134]

[0159] Embodiment 55: The active agent of embodiment 54, wherein the active agent is mivolilaner.

[0160] Embodiment 56: The active substance of embodiment 55, wherein the predetermined dosage amount is multiplied by about 0.125 to about 0.9.

[0135]

[0161] Embodiment 57: The active substance of embodiment 55, wherein the maximum concentration of the active substance in the blood of the mammal is reached to less than about 20% of the maximum blood concentration reached when a predetermined dose of the active substance is administered to the mammal at intervals of one month or more.

[0136]

[0162] Embodiment 58: An active substance for use in the control of flea and / or tick infestations in mammals, comprising the active agent has a predetermined dosage for oral administration to a mammal for controlling fleas and / or ticks, the predetermined dosage of the active agent being for a predetermined administration regime of once every 30 days or once a month; The given dose is multiplied by about 0.90 or less to obtain the reduced dose; The reduced dose is converted into a reduced daily dose, A reduced daily dosage of the active agent is administered to the mammal substantially daily for several days; An active substance which, after administration over several days, controls the flea and / or tick population on a mammal to the same or greater extent than when a predetermined dosage of the active substance is administered to the mammal at intervals of once every 30 days or once a month.

[0137]

[0163] Embodiment 59: The active substance of embodiment 58, wherein the predetermined dosage amount is multiplied by about 0.20 to about 0.90.

[0164] Embodiment 60: The active substance of any of embodiments 58-59, wherein the predetermined dosage amount is multiplied by about 0.70 or less.

[0138]

[0165] Embodiment 61: The active substance of any of embodiments 58 to 60, wherein the predetermined dosage amount is multiplied by about 0.50 or less.

[0166] Embodiment 62: The active agent of any of embodiments 58 to 61, wherein the active agent is selected from the group consisting of spinosyns and isoxazolines.

[0139]

[0167] Embodiment 63: The active agent of embodiment 62, wherein the active agent is a spinosyn.

[0168] Embodiment 64: The active agent of embodiment 63, wherein the spinosyn is spinosad.

[0140]

[0169] Embodiment 65: The active substance according to embodiment 64, wherein the given dosage is multiplied by about 12.5% ​​to 90%.

[0170] Embodiment 66: An active substance according to embodiment 63, wherein the given dosage controls fleas but not mites, and wherein a reduced daily dosage controls fleas and mites.

[0141]

[0171] Embodiment 67: The active agent of embodiment 58, wherein the active agent is an isoxazoline.

[0172] Embodiment 68: The active substance according to embodiment 67, wherein the isoxazoline is selected from the group consisting of mivolilaner, fluralaner, sarolaner, afoxolaner, lotilaner, tigolaner, umifoxolaner, esafoxolaner, modofuraner, and salts thereof.

[0142]

[0173] Embodiment 69: The active agent of embodiment 68, wherein the active agent is mivolilaner.

[0174] Embodiment 70: The active substance of embodiment 69, wherein the predetermined dosage amount is multiplied by about 0.125 to about 0.9.

[0143]

[0175] Embodiment 71: The active substance according to any of embodiments 58 to 70, wherein the active substance is an ingredient of a feed.

[0176] Embodiment 72: The active agent of any of embodiments 58 to 70, wherein the active agent is a component of a chew.

[0144]

[0177] Embodiment 73: The active substance according to any of embodiments 58 to 72, wherein the reduced daily dose is between 1 / 10 and 1 / 30 of the reduced dose.

[0178] Embodiment 74: The active substance according to embodiment 73, wherein the reduced daily dose is between 1 / 15 and 1 / 30 of the reduced dose.

[0145]

[0179] Embodiment 75: The active substance of embodiment 74, wherein the reduced daily dose is about 1 / 30 of the reduced dose.

[0180] In certain aspects of any of the embodiments in which the active agent is an isoxazoline, administration to control tick infestation provides a therapeutically effective concentration of the particular isoxazoline in the blood of the mammal for at least 30 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivorilaner provides an isoxazoline concentration of greater than about 400 ng / mL and less than about 4000 ng / mL in the blood of the mammal for at least 30 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 20 ng / mL and less than about 800 ng / mL in the blood of the mammal for at least 30 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 30 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 30 days. In another example, Lotilaner provides an isoxazoline concentration of greater than about 80 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 30 days. In another example, Tigolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 30 days. In another example, Umifoxolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 30 days. In another example, Esafoxolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 400 ng / mL in the blood of the mammal for at least 30 days.

[0146]

[0181] In certain aspects of any of the embodiments in which the active agent is an isoxazoline, administration to control tick infestation provides a therapeutically effective concentration of the particular isoxazoline in the blood of the mammal for at least 365 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivoliraner provides an isoxazoline concentration of greater than about 400 ng / mL and less than about 4000 ng / mL in the blood of the mammal for at least 365 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 20 ng / mL and less than about 800 ng / mL in the blood of the mammal for at least 365 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 365 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 365 days. In another example, Lotilaner provides an isoxazoline concentration of greater than about 80 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 365 days. In another example, Tigolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 365 days. In another example, Umifoxolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 365 days. In another example, Esafoxolaner provides an isoxazoline concentration of greater than about 10 ng / mL and less than about 400 ng / mL in the blood of the mammal for at least 365 days.

[0147]

[0182] In certain aspects of any of the embodiments in which the active agent is an isoxazoline, administration to control flea infestation provides a therapeutically effective concentration of the particular isoxazoline in the blood of the mammal for at least 30 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2500 ng / mL in the blood of the mammal for at least 30 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 30 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 1500 ng / mL in the blood of the mammal for at least 30 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 400 ng / mL in the blood of the mammal for at least 30 days. In another example, Lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 30 days. In another example, Tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 30 days. In another example, Umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 30 days. In another example, Esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 30 days.

[0148]

[0183] In certain aspects of any of the embodiments in which the active agent is an isoxazoline, administration to control flea infestation provides a therapeutically effective concentration of the particular isoxazoline in the blood of the mammal for at least 365 days. The exact concentration may vary depending on the particular isoxazoline. For example, administration of mivoliraner provides an isoxazoline concentration of greater than about 40 ng / mL and less than about 2500 ng / mL in the blood of the mammal for at least 365 days. In another example, afoxolaner provides an isoxazoline concentration of greater than about 2 ng / mL and less than about 600 ng / mL in the blood of the mammal for at least 365 days. In another example, fluralaner provides an isoxazoline concentration of greater than about 4 ng / mL and less than about 1500 ng / mL in the blood of the mammal for at least 365 days. In another example, sarolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 400 ng / mL in the blood of the mammal for at least 365 days. In another example, Lotilaner provides an isoxazoline concentration of greater than about 8 ng / mL and less than about 2000 ng / mL in the blood of the mammal for at least 365 days. In another example, Tigolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 365 days. In another example, Umifoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 365 days. In another example, Esafoxolaner provides an isoxazoline concentration of greater than about 1 ng / mL and less than about 300 ng / mL in the blood of the mammal for at least 365 days.

[0149]

[0184] In certain aspects of any of the embodiments in which the active agent is a spinosyn, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 6000 ng / mL for at least 30 days. More preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 2500 ng / mL for at least 30 days. Even more preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 2000 ng / mL for at least 30 days. Even more preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 400 ng / mL and less than about 1500 ng / mL for at least 30 days.

[0150]

[0185] In certain aspects of any of the embodiments in which the active agent is a spinosyn, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 6000 ng / mL for at least 365 days. More preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 2500 ng / mL for at least 365 days. Even more preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 300 ng / mL and less than about 2000 ng / mL for at least 365 days. Even more preferably, administration provides a spinosyn concentration in the blood of said mammal of greater than about 400 ng / mL and less than about 1500 ng / mL for at least 365 days.

[0151]

[0186] In some aspects of any of the embodiments in which the active agent is a spinosyn, administration for controlling flea infestation maintains a spinosyn concentration of at least 5 ng / ml and no more than 600 ng / ml in the blood of said canine for at least 30 days. More preferably, administration maintains a spinosyn concentration of at least 5 ng / ml and no more than 300 ng / ml in the blood of said canine for at least 30 days. More preferably, administration maintains a spinosyn concentration of at least 10 ng / ml and no more than 225 ng / ml in the blood of said mammal for at least 30 days. Even more preferably, administration maintains a spinosyn concentration of at least 25 ng / ml and no more than 200 ng / ml in the blood of said mammal for at least 30 days.

[0152]

[0187] In some aspects of any of the embodiments in which the active agent is a spinosyn, administration for controlling flea infestation maintains a spinosyn concentration of at least 5 ng / ml and no more than 600 ng / ml in the blood of said canine for at least 365 days. More preferably, administration maintains a spinosyn concentration of at least 5 ng / ml and no more than 300 ng / ml in the blood of said canine for at least 365 days. Even more preferably, administration maintains a spinosyn concentration of at least 10 ng / ml and no more than 225 ng / ml in the blood of said mammal for at least 365 days. Even more preferably, administration maintains a spinosyn concentration of at least 25 ng / ml and no more than 200 ng / ml in the blood of said mammal for at least 365 days. EXAMPLES

[0153]

[0188] The following examples illustrate the methods of the present disclosure. Example 1

[0189] Efficacy of spinosyns administered orally, i.e. by mouth, to dogs for the treatment and control of Rhipicephalus sanguineus

[0190] Methods: A pool of 40 dogs is pre-infested with approximately 100 unfed adult C. felis to create a pool of dogs that can adequately maintain a reliable infestation rate of approximately 50% live fleas over a 48 hour period. Dogs with the highest live flea counts are randomly assigned to two treatment groups (6 dogs per group) based on their pre-treatment flea counts from the trial infestation. The first treatment group is the control group and the second treatment group is the test group.

[0154]

[0191] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0192] Each dog in the test group is given a liquid formulation of a spinosyn, preferably spinosad, by mouth at a dose of 2.5 mg / kg of the dog's weight on each of days 0-29 and at a dose of 5 mg / kg of the dog's weight on days 30-50.

[0155]

[0193] Dogs in the control group receive no spinosyns or any other tick control treatment. Each dog in the test group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of spinosyns is administered, the dog is allowed to continue eating. This is similar to incorporating spinosyns in the diet. Each dog in the test and control groups is challenge infested with 50 unfed adult ticks (approximately 50% male / 50% female) on test days 12, 19, 28, 35, 42, 49, and 56. Counts of attached live and moribund adult ticks are taken on days 14, 21, 30, 37, 44, 51, and 58. Note that the dose is escalated on day 30 and the final dose is administered on day 50.

[0156]

[0194] Results: The percent reduction in attached live and moribund adult tick counts in the test groups compared to the control groups with spinosad is shown in the graph below.

[0157] [ka]

[0158]

[0195] Using the same study methodology described above, blood is drawn at 72, 120, 168, 336, 504, 720 and 888 hours after the initial dose of Spinosyn is administered. The average blood concentrations of Spinosyn at the different dose levels can then be determined.

[0159]

[0196] Sample results of mean plasma concentrations of spinosad in canine blood at different dose levels are shown in the following table and figure. For comparison, mean plasma concentrations of spinosad following a single monthly dose are also shown in the following table and figure.

[0160] [Table 1]

[0161] [ka]

[0162] Example 2

[0197] Efficacy of spinosyns administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0198] Methods: A pool of 40 dogs was pre-infested with approximately 100 unfed adult C. felis to create a pool of dogs that could adequately maintain a reliable infestation rate of approximately 50% live fleas over a 48-hour period. Dogs with the highest live flea counts were randomly assigned to four treatment groups (six dogs per group) based on their pre-treatment flea counts from the trial infestation. The first treatment group was the control group and groups 2-4 were the test groups.

[0163]

[0199] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0200] Each dog in test groups 2-4 is given a liquid formulation of a spinosyn, preferably spinosad, by mouth. The dog is administered a dose on each of days 0-29 according to the test group as shown in the table below.

[0164] [Table 2]

[0165]

[0201] Dogs in the control group receive no Spinosyn or any other flea control treatment. Each dog in test groups 2-4 is fed its daily diet (dry food) and administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of Spinosyn is administered, the dog is allowed to continue eating. This is similar to incorporating Spinosyn in the diet. Each dog in test groups 2-4 and the control group is challenge infested with 100 unfed adult fleas on test days 1, 5, 12, 19, 28, and 35. Combined counts of live adult fleas are taken on days 2, 7, 14, 21, 30, and 37. A final challenge infestation occurs 5 days after the last daily dose of Spinosyn.

[0166]

[0202] Results: The percent reduction in live adult flea counts by spinosad for test groups 2-4 is shown in the graph below.

[0167] [ka]

[0168]

[0203] Using the same study methodology described above, blood is drawn at 72, 120, 168, 336, 504, 720 and 888 hours after the initial dose of Spinosyn is administered. The average blood concentrations of Spinosyn at the different dose levels can then be determined.

[0169]

[0204] Sample results of mean plasma concentrations of spinosad in canine blood at different dose levels are shown in the table and figure below.

[0170] [Table 3]

[0171] [ka]

[0172]

[0205] For comparison, the mean plasma concentrations of spinosad following a single dose given monthly are shown in the figure below.

[0173] [ka]

[0174] Example 3

[0206] Efficacy of spinosyns in dogs when administered in medicated feed at a dose of 0.5 mg / kg of dog weight

[0207] Methods: To create a pool of 18 dogs that could adequately maintain a reliable infestation rate of approximately 50% live fleas over a 48-hour period, the pool of dogs was pre-infested with approximately 100 unfed adult C. felis. Dogs with the highest live flea counts were randomly assigned to three groups (six dogs per group) based on their pre-treatment flea counts from the trial infestation. The first treatment group was the control group and groups 2-3 were the test groups.

[0175]

[0208] Dogs are individually housed for the duration of the study with water available ad libitum.

[0209] There is an initial acclimation period of at least 4 days during which dogs in study groups 2 and 3 are transitioned from the standard certified commercial food to a non-medicated version of the daily diet. During the acclimation period, dogs are given 1 hour to consume food, after which the dogs' acceptance of the food is observed and recorded.

[0176]

[0210] Each dog in test groups 2 and 3 is fed orally a daily feed formulation containing a spinosyn, preferably spinosad. The doses and formulations administered to the dogs on each of days 0-29 according to test group are shown in the table below.

[0177] [Table 4]

[0178]

[0211] Dogs in the control group receive no Spinosyns or any other flea control treatment. On days 0-29, each dog in test groups 2 and 3 is fed its daily food containing Spinosyns for 1 hour. On days 30-37, all dogs are fed regular dog food that does not contain Spinosyns or physiologically acceptable derivatives thereof.

[0179]

[0212] Each dog in test groups 2 and 3 and the control group is challenged with 100 unfed adult fleas on test days 1, 5, 12, 28 and 35. Combined live adult flea counts are taken on days 2, 7, 14, 30 and 37.

[0180]

[0213] Results: In the sample study with diets containing spinosad, all dogs in groups 2 and 3 consumed all food required for the 0.5 mg / kg dose within 1 hour without regurgitation. The percent reduction in live adult flea count samples in test groups 2 and 3 due to spinosad is shown in the graph below.

[0181] [ka]

[0182]

[0214] From this example it can be seen that even if some daily doses are missed, an effective amount of spinosyn can be administered to the dog via the medicated feed to control the flea infestation.

[0183] Example 4

[0215] Efficacy of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Rhipicephalus sanguineus.

[0216] Methods: To generate dogs capable of adequately maintaining a reliable infestation rate defined as approximately 50% of fleas alive at the end of 48 hours, a pool of 14 dogs is pre-infested with approximately 100 unfed adult C. felis. The 12 dogs with the highest live flea counts are selected for inclusion in the study. Dogs are divided into control and test groups.

[0184]

[0217] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0218] Each dog in the treatment group is given a liquid formulation of isoxazoline by mouth. A dose of 0.75 mg / kg is administered to the dogs on each of days 0-29.

[0185]

[0219] Control dogs receive no isoxazoline or any other tick control treatment. Each dog in the treatment group is provided with its daily feed (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily feed. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating isoxazoline in the feed. Each dog in the treatment and control groups is challenged with 50 adult ticks on test days 5, 12, 19, 28, and 35. Combined counts of live and moribund attached ticks are taken on days 7, 14, 21, 30, and 37.

[0186]

[0220] Results: The percentage reduction in live and moribund attached tick counts in treatment groups with Mivorilaner is shown in the graph below.

[0187] [ka]

[0188]

[0221] Using the same study methodology described above, blood is drawn at 72, 168, 336, 504, 720 and 888 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0189]

[0222] Sample results of mean plasma concentrations of mivorilaner in canine blood at different dose levels are shown in the table and figure below.

[0190] [Table 5]

[0191] [ka]

[0192] Example 5

[0223] Efficacy of various doses of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Rhipicephalus sanguineus

[0224] Methods: A pool of 46 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to generate dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 40 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0193]

[0225] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0226] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-59.

[0194] [Table 6]

[0195]

[0227] Dogs in the control group receive no isoxazoline or any other tick control treatment. Each dog in the treatment group is fed its daily diet (dry food) and administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating isoxazoline in the diet. Each dog in treatment groups 3-5 and the control group is challenged with 50 adult mites on test days 2, 5, 12, 19, 28, 35, and 42. Dogs in group 2 are challenged with 50 adult mites on test days 19, 28, and 35. Combined live adult tick counts are taken on days 2, 7, 14, 21, 30, 37, and 44.

[0196]

[0228] Results: The percentage reduction in live and moribund attached tick counts in the treatment groups for Mivorilaner is shown in the graph below.

[0197] [ka]

[0198]

[0229] Using the same study methodology described above, blood is drawn at 0, 72, 120, 168, 336, 504, 720, 888, 1056, 1224 and 1440 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0199]

[0230] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0200] [Table 7]

[0201] [ka]

[0202] Example 6

[0231] Comparison of plasma concentrations of isoxazolines in dogs when administered intravenously and orally in solution and crystal form

[0232] Methods: A pool of 24 dogs, 50% female, 50% male, 6 juveniles and 28 adults, are assigned to 4 study groups according to the table below.

[0203] [Table 8]

[0204]

[0233] Dogs are allowed free access to water. On day 1 of the study, prior to administration of the isoxazoline, juvenile dogs are fed approximately 25% of their daily diet as canned food. Four hours later, juvenile dogs are fed the remainder of their daily diet as dry food. On day 1 of the study, prior to administration, adult dogs are fed approximately 1 / 3 can of dog food and the remainder of their daily diet following the 10 hour blood collection time point. For the remainder of the study, all dogs' daily diets should be fed over approximately 2 hours.

[0205]

[0234] On day 1 of the study, dogs are given one dose of the isoxazoline in a fed state. Dogs are fasted prior to treatment (young animals are fasted for less than 10 hours). The isoxazoline treatment is administered within approximately 30 minutes once the dog is observed to have eaten 25% of its daily ration. This is similar to incorporating the isoxazoline in the feed.

[0206]

[0235] Blood samples are taken for test groups 1 and 2 (administered intravenously) at 0, 0.083, 0.25, 0.5, 1, 3, 6, 10, 24, 48 and 96 hours after initial treatment and at 7, 10, 14, 21, 28 and 32 days after initial treatment. Blood samples are taken for test groups 3 and 4 (administered orally) at 0, 0.25, 0.5, 1, 3, 6, 10, 24, 48 and 96 hours after initial treatment and at 7, 10, 14, 21, 28 and 32 days after initial treatment. After the first sample on day 1, dogs are fasted for a minimum of 4 hours before further blood samples are taken.

[0207]

[0236] Results: The mean plasma concentrations in a study conducted with mivoliraner similar to this example are shown in the figure below.

[0208] [ka]

[0209] Example 7

[0237] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Rhipicephalus sanguineus.

[0238] Methods: A pool of 36 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to generate dogs capable of adequately maintaining a reliable infestation rate defined as approximately 25% attached ticks alive at the end of 48 hours. The 30 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0210]

[0239] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0240] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-20.

[0211] [Table 9]

[0212]

[0241] Control dogs receive no isoxazoline or any other tick control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 50 unfed adult ticks on test days 2, 5, 12, 19, and 28. Combined counts of attached live and moribund adult ticks are taken on days 2, 7, 14, 21, and 30.

[0213]

[0242] Results: The percentage reduction in attached live tick and attached moribund tick counts for treatment groups according to this example is shown in the graph below.

[0214] [ka]

[0215] Example 8

[0243] Plasma concentrations of isoxazolines in dogs when administered in medicated feed at a dose of 1.0 mg / kg of dog weight per day

[0244] Methods: A pool of 30 dogs will be assigned by weight into 5 groups to minimize between- and within-group variability. Each group will be fed a different feed formulation containing the isoxazoline, and blood levels of the isoxazoline will be determined over a one-month period after a single dose.

[0216]

[0245] Dogs are individually housed for the duration of the study with water available ad libitum.

[0246] There is an initial acclimation period of at least 4 days during which dogs are transitioned from the standard certified commercial food to a non-medicated version of the daily diet. During the acclimation period, dogs are allowed to consume food for 15 min / day.

[0217]

[0247] On day 1 of the study, dogs are given approximately 9.4 g / kg of isoxazoline-containing chow daily. The amount of drugged chow for each dog is determined according to the dog's most recent body weight prior to the day of the study. The drugged chow is offered for 15 minutes at the start of the study. Any uneaten drugged chow is removed and weighed. An amount of undrugged chow equal to the amount of uneaten drugged chow is offered at the time of the first blood draw 10 hours later.

[0218]

[0248] Blood samples are collected at the following times: 0 hours (at the time of drugged food presentation), 0.25 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 10 hours, 1 day, 2 days, 4 days, 6 days, 9 days, 13 days, 20 days, 27 days and 31 days after drugged food presentation.

[0219]

[0249] Results: The mean plasma concentrations in a study conducted with mivoliraner similar to this example are shown in the table and figure below.

[0220] [Table 10]

[0221] [ka]

[0222]

[0250] By comparing the above examples, it can be seen that on average an effective amount of isoxazoline can be administered to a dog via the medicated feed. Example 9

[0251] Efficacy of isoxazolines when administered in medicated feed for the treatment and control of Rhipicephalus sanguineus.

[0252] Methods: A pool of dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to generate dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 72 hours. The 24 dogs with the highest live attached tick counts are selected for inclusion in the study. The 18 dogs with the highest live attached tick counts are randomly assigned to one control group and two treatment groups. The next 6 dogs with the highest live attached tick counts are assigned to a third treatment group.

[0223]

[0253] Dogs are individually housed for the duration of the study with water available ad libitum.

[0254] Each dog in the treatment group (study groups 2-4) will be provided with a daily medicated chow on study days 0 through 49. Depending on the study group, the daily medicated chow will be provided to the dog for a 1-h period on each of days 0 through 49.

[0224] [Table 11]

[0225]

[0255] Dogs in the control group receive no isoxazoline or any other tick control treatment. Each dog in treatment groups 2 and 3 and the control group is challenged with 50 unfed adult ticks on test days 2, 4, 12, and 28 during the treatment phase, and on days 52, 56, and 62 during the washout period following the last feeding of the medicated daily food. Counts of attached live and moribund adult ticks are taken on days 3, 8, 15, 30, 54, and 58.

[0226]

[0256] Results: The percent reduction in live adult tick counts for the treatment groups according to this example for Mivorilaner is shown in the graph below.

[0227] [ka]

[0228]

[0257] Using the same study methodology described above, blood is drawn at 0, 1, 3, 6, 10, 24, 48, 96, 168, 240, and 336 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0229]

[0258] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0230] [Table 12]

[0231] [ka]

[0232] Example 10

[0259] Efficacy of various doses of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis

[0260] Methods: A pool of 14 dogs is pre-infested with approximately 100 unfed adult C. felis to identify dogs capable of adequately maintaining a reliable infestation rate defined as approximately 50% of fleas alive at the end of 48 hours. The 12 dogs with the highest live flea counts are selected for inclusion in the study. Dogs are divided into control and treatment groups.

[0233]

[0261] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0262] Each dog in the treatment group is given a liquid formulation of isoxazoline by mouth. A dose of 0.75 mg / kg is administered to the dogs on each of days 0-29.

[0234]

[0263] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 2, 5, 12, 20, and 35. Combined counts of live adult fleas are taken on days 4, 7, 14, 21, and 37.

[0235]

[0264] Results: The percent reduction in live adult flea counts in treatment groups with mivorilaner is shown in the graph below.

[0236] [ka]

[0237]

[0265] Using the same study methodology described above, blood is drawn at 72, 168, 336, 504, 720 and 888 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0238]

[0266] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0239] [Table 13]

[0240] [ka]

[0241] Example 11

[0267] Efficacy of various doses of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis

[0268] Methods: A pool of 46 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 40 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0242]

[0269] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0270] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-59.

[0243] [Table 14]

[0244]

[0271] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, 12, 19, 28, 35, and 42. Combined counts of live adult fleas are taken on days 2, 7, 14, 21, 30, 37, and 44.

[0245]

[0272] Results: The percent reduction in live adult flea counts in the treatment groups for mivorilaner is shown in the graph below.

[0246] [ka]

[0247]

[0273] Using the same study methodology described above, blood is drawn at 0, 72, 120, 168, 336, 504, 720, 888, 1056, 1224 and 1440 hours after the initial dose of isoxazoline is administered. The average blood concentrations of isoxazoline at different dose levels can then be determined.

[0248]

[0274] Sample results of mean plasma concentrations of isoxazoline in canine blood at different dose levels for mivorilaner are shown in the table and figure below.

[0249] [Table 15]

[0250] [ka]

[0251] Example 12

[0275] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0276] Methods: A pool of 36 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 30 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0252]

[0277] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0278] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-20.

[0253] [Table 16]

[0254]

[0279] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, and 28. Combined counts of live adult fleas are taken on days 2, 7, and 30.

[0255]

[0280] Results: The percent reduction in live adult flea counts for treatment groups according to this example is shown in the graph below.

[0256] [ka]

[0257] Example 13

[0281] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Rhipicephalus sanguineus.

[0282] Methods: A pool of 24 dogs is pre-infested with approximately 50 unfed adult R. sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 20 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0258]

[0283] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0284] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-27.

[0259] [Table 17]

[0260]

[0285] Control dogs receive no isoxazoline or any other tick control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult ticks on test days 2, 5, 12, 19, 28, and 33. Combined counts of live and moribund attached adult ticks are taken on days 2, 7, 14, 21, 30, and 35.

[0261]

[0286] Results: The percentage reduction in live and moribund adult tick counts for treatment groups according to this example is shown in the graph below.

[0262] [ka]

[0263] Example 14

[0287] Efficacy of various formulations of isoxazolines administered orally, i.e. by mouth, to dogs for the treatment and control of Ctenocephalides felis.

[0288] Methods: A pool of 24 dogs is pre-infested with approximately 50 unfed adult Rhipicephalus sanguineus ticks to identify dogs capable of adequately maintaining a reliable infestation rate defined by approximately 25% attached ticks alive at the end of 48 hours. The 20 dogs with the highest live attached tick counts are selected for inclusion in the study. Dogs are randomly assigned to one control group and four treatment groups.

[0264]

[0289] Dogs are individually housed for the duration of the study, fed a commercial dry dog ​​food diet, and allowed free access to water.

[0290] Each dog in the treatment group (test groups 2-5) is given a liquid formulation of isoxazoline by mouth. Depending on the test group, a dose is administered to the dog on each of days 0-27.

[0265] [Table 18]

[0266]

[0291] Dogs in the control group receive no isoxazoline or any other flea control treatment. Each dog in the treatment group is provided with its daily diet (dry food) and is administered an individual dose of the liquid formulation after each dog has eaten at least 25% of its total daily diet. After the dose of isoxazoline is administered, the dog is allowed to continue eating. This is similar to incorporating the isoxazoline in the diet. Each dog in the treatment and control groups is challenged with 100 unfed adult fleas on test days 1, 5, and 33. Combined counts of live adult fleas are taken on days 2, 7, and 35.

[0267]

[0292] Results: The percent reduction in live adult flea counts for treatment groups according to this example is shown in the graph below.

[0268] [ka]

[0269]

[0293] While the invention has been described in an illustrative manner, the invention may be further modified within the spirit and scope of the disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles.

Claims

1. A method for establishing a regimen for orally administering a reduced dosage of an active agent for controlling flea and / or tick infestation in a mammal, comprising: (a) selecting an active agent having a predetermined dosage for oral administration to a mammal for controlling fleas and / or ticks, said predetermined dosage being for a predetermined dosing regimen of once every 30 days or once a month; (b) multiplying the predetermined dose by no more than about 0.90 to obtain a reduced dose; (c) calculating a reduced daily dose from the reduced dose; and (d) providing instructions for administering said active agent at said reduced daily dosage to said mammal substantially daily for several days; whereby, after following the administration instructions, the flea and / or tick infestation of the mammal is controlled to the same or greater extent than when the predetermined dosage of active substance is administered to the mammal at said 30 day or monthly intervals.

2. The method of claim 1, wherein step (b) comprises multiplying the predetermined dose by between about 0.20 and about 0.

90.

3. The method of claim 1, wherein step (b) comprises multiplying the predetermined dose by about 0.70 or less.

4. The method of claim 1, wherein step (b) comprises multiplying the predetermined dose by about 0.50 or less.

5. The method of claim 1, wherein the active substance is a spinosyn.

6. The method of claim 5, wherein the spinosyn is spinosad.

7. The method of claim 5, wherein step (b) comprises multiplying the predetermined dose by approximately 12.5% ​​to 90%.

8. The method of claim 7, wherein the predetermined dosage controls fleas but not mites, and the reduced daily dosage controls fleas and mites.

9. The method of claim 5, wherein carrying out steps (a) to (d) results in a maximum concentration of the active agent in the blood of the mammal that reaches less than about 10% of the maximum blood concentration that would be reached if the predetermined dose of the active agent were administered to the mammal at intervals of once every 30 days or once a month.

10. The method of claim 1, wherein the active agent is an isoxazoline.

11. The method of claim 10, wherein the isoxazoline is selected from the group consisting of mivorilaner, fluralaner, sarolaner, afoxolaner, lotilaner, tigolaner, umifoxolaner, esafoxolaner, modofuraner, and salts thereof.

12. The method according to claim 11, wherein the active substance is mivorilaner.

13. The method of claim 12, wherein step (b) comprises multiplying the predetermined dose by about 0.125 to about 0.

9.

14. The method of claim 13, wherein carrying out steps (a) to (d) results in a maximum concentration of the active agent in the blood of the mammal that reaches less than about 20% of the maximum blood concentration that would be reached if the predetermined dose of the active agent were administered to the mammal at said 30 day or monthly intervals.

15. A composition for controlling flea and / or tick infestation in a mammal in need thereof, comprising: The following steps: orally administering to said mammal an effective amount of an active agent; continuing said oral administration substantially daily for several days, thereby raising a blood concentration of said active agent in said mammal to an amount effective to reduce said flea and / or tick infestation; and ceasing said oral administration for a period of at least one day after said mammal has reached a blood concentration of said active agent effective to reduce said flea or tick infestation, wherein said mammal's blood concentration of active agent remains effective to control said flea and / or tick infestation over said period. The composition used for 16. The composition of claim 15, wherein the active substance is a spinosyn.

17. The composition of claim 15, wherein the active substance is spinosad.

18. A feed comprising an effective amount of an active substance for controlling flea and / or tick infestation in a mammal in need of control thereof, comprising: wherein oral administration of said feed is continued substantially daily for several days, thereby increasing a blood concentration of said active agent in said mammal to an amount effective to reduce said flea and / or tick infestation; said daily oral administration of said feed is discontinued for a period of at least one day after said mammal's blood concentration of said active agent has reached an amount effective to reduce said flea or tick infestation, and said mammal's blood concentration of active agent remains effective to control said flea and / or tick infestation for said period.

19. The feed described in claim 18, wherein the active substance is a spinosyn.

20. The feed of claim 18, wherein the active substance is spinosad.

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