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    Mean ± SD plasma selamectin concentrations in healthy New Zealand White rabbits after topical administration of 1 dose of selamectin at 10 (black circles; n = 6) or 20 (white circles; 6) mg/kg. Numbers in parentheses indicate the number of samples with selamectin concentrations above the LLOQ of the analytic assay (5 ng/mL) if < 6 samples/time point. The day of drug administration was considered day 0.

  • 1.

    AVMA. U.S. pet ownership & demographics sourcebook. Schaumburg, Ill: AVMA, 2007;1159.

  • 2.

    Revolution [package insert]. Exton, Pa: Pfizer Animal Health, 2011.

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    Sarasola P, Jernigan AD, Walker DK, et al. Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs. J Vet Pharmacol Ther 2002; 25:265272.

    • Search Google Scholar
    • Export Citation
  • 4.

    McTier TL, Shanks DJ, Jernigan AD, et al. Evaluation of the effects of selamectin against adult and immature stages of fleas (Ctenocephalides felis felis) on dogs and cats. Vet Parasitol 2000; 91:201212.

    • Search Google Scholar
    • Export Citation
  • 5.

    Boy MG, Six RH, Thomas CA, et al. Efficacy and safety of selamectin against fleas and heartworms in dogs and cats presented as veterinary patients in North America. Vet Parasitol 2000; 91:233250.

    • Search Google Scholar
    • Export Citation
  • 6.

    Shanks DJ, Gautier P, McTier TL, et al. Efficacy of selamectin against biting lice on dogs and cats. Vet Rec 2003; 152:234237.

  • 7.

    Chailleux N & Paradis M. Efficacy of selamectin in the treatment of naturally acquired cheyletiellosis in cats. Can Vet J 2002; 43:767770.

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    • Export Citation
  • 8.

    Mueller RS, Bettenay SV. Efficacy of selamectin in the treatment of canine cheyletiellosis. Vet Rec 2002; 151:773.

  • 9.

    McTier TL, Hair JA, Walstrom DJ, et al. Efficacy and safety of topical administration of selamectin for treatment of ear mite infestation in rabbits. J Am Vet Med Assoc 2003; 223:322324.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kurtdede A, Karaer Z, Acar A, et al. Use of selamectin for the treatment of psoroptic and sarcoptic mite infestation in rabbits. Vet Dermatol 2007; 18:1822.

    • Search Google Scholar
    • Export Citation
  • 11.

    Farmaki R, Koutinas AF, Papazahariadou MG, et al. Effectiveness of a selamectin spot-on formulation in rabbits with sarcoptic mange. Vet Rec 2009; 164:431432.

    • Search Google Scholar
    • Export Citation
  • 12.

    Mellgren M & Bergvall K. Treatment of rabbit cheyletiellosis with selamectin or ivermectin: a retrospective case study. Acta Vet Scand 2008; 50:16.

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  • 13.

    Kim S-H, Lee J-Y, Jun H-K, et al. Efficacy of selamectin in the treatment of cheyletiellosis in pet rabbits. Vet Dermatol 2007; 19:2627.

  • 14.

    Hughes JE. Diagnosis and treatment of selected rabbit dermatologic disorders. Exot DVM 2004; 5(6):1820.

  • 15.

    Van Praag E. Parasites affecting rabbits: fleas. Available at www.medirabbit.com/EN/Skin_diseases/Parasitic/fleas/Fleas.htm. Accessed June 15, 2010.

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  • 16.

    Fisher M, Beck W, Hutchinson MJ. Efficacy and safety of selamectin (Stronghold/Revolution) used off-label in exotic pets. Int J Appl Res Vet Med 2007; 5:8796.

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  • 17.

    Harcourt-Brown F. Textbook of rabbit medicine. Oxford, England: Butterworth-Heinemann, 2002;111112, 361.

  • 18.

    Morrisey JK. Rabbits. In: Carpenter J W, ed. Exotic animal formulary. St Louis: Elsevier/Saunders, 2005;407444.

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    Krautmann MJ, Novotny MJ, DeKeulenaer K, et al. Safety of selamectin in cats. Vet Parasitol 2000; 91:393403.

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    Novotny MJ, Krautman MJ, Ehrhart JC, et al. Safety of selamectin in dogs. Vet Parasitol 2000; 91:377391.

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Pharmacokinetics, efficacy, and adverse effects of selamectin following topical administration in flea-infested rabbits

James W. Carpenter MS, DVM1, Michael W. Dryden DVM, PhD2, and Butch KuKanich DVM, PhD3
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  • 1 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 2 Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 3 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Abstract

Objective—To determine pharmacokinetics, efficacy, and adverse effects of topically administered selamectin in flea-infested rabbits.

Animals—18 healthy 5-month-old New Zealand White rabbits.

Procedures—On day 0, rabbits (n = 6/group) received topically applied selamectin at doses of 10 or 20 mg/kg or received no treatment. Each rabbit was infested with 50 fleas (Ctenocephalides felis) on days −1, 7, and 14. Live and dead flea counts were performed on days 2, 9, and 16, and treatment efficacy was calculated. Blood samples were collected prior to drug administration and at 6 and 12 hours and 1, 2, 3, 5, 7, 10, 14, 21, and 28 days after treatment for determination of plasma selamectin concentrations via high-performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were determined.

Results—On day 2, efficacy of selamectin against flea populations of rabbits in the 10 and 20 mg/kg treatment groups was 91.3% and 97.1%, respectively, but by day 9, these values decreased to 37.7% and 74.2%, respectively. Mean terminal half-life and maximum plasma concentrations of selamectin were 0.93 days and 91.7 ng/mL, respectively, for rabbits in the 10 mg/kg group and 0.97 days and 304.2 ng/mL, respectively, for rabbits in the 20 mg/kg group. No adverse effects were detected.

Conclusions and Clinical Relevance—Selamectin was rapidly absorbed transdermally and was rapidly eliminated in rabbits. Results suggested that topical administration at a dosage of 20 mg/kg every 7 days is efficacious for treatment of flea infestation in rabbits. Further studies are needed to assess long-term safety in rabbits following repeated applications.

Abstract

Objective—To determine pharmacokinetics, efficacy, and adverse effects of topically administered selamectin in flea-infested rabbits.

Animals—18 healthy 5-month-old New Zealand White rabbits.

Procedures—On day 0, rabbits (n = 6/group) received topically applied selamectin at doses of 10 or 20 mg/kg or received no treatment. Each rabbit was infested with 50 fleas (Ctenocephalides felis) on days −1, 7, and 14. Live and dead flea counts were performed on days 2, 9, and 16, and treatment efficacy was calculated. Blood samples were collected prior to drug administration and at 6 and 12 hours and 1, 2, 3, 5, 7, 10, 14, 21, and 28 days after treatment for determination of plasma selamectin concentrations via high-performance liquid chromatography with mass spectrometry. Pharmacokinetic parameters were determined.

Results—On day 2, efficacy of selamectin against flea populations of rabbits in the 10 and 20 mg/kg treatment groups was 91.3% and 97.1%, respectively, but by day 9, these values decreased to 37.7% and 74.2%, respectively. Mean terminal half-life and maximum plasma concentrations of selamectin were 0.93 days and 91.7 ng/mL, respectively, for rabbits in the 10 mg/kg group and 0.97 days and 304.2 ng/mL, respectively, for rabbits in the 20 mg/kg group. No adverse effects were detected.

Conclusions and Clinical Relevance—Selamectin was rapidly absorbed transdermally and was rapidly eliminated in rabbits. Results suggested that topical administration at a dosage of 20 mg/kg every 7 days is efficacious for treatment of flea infestation in rabbits. Further studies are needed to assess long-term safety in rabbits following repeated applications.

Nontraditional pets are rapidly becoming an integral part of many companion animal practices, and more households report owning rabbits than any other exotic mammal.1 In addition, the amount of financial resources that owners are spending on rabbit care is also increasing.1

Lack of pharmacokinetic, efficacy, and safety data for chemotherapeutics in small mammals can be very problematic because veterinarians may need to use agents approved for other species and extrapolate their safety and efficacy to small mammals without a scientific basis. The rate and extent of absorption as well as the rate of elimination and persistence of drugs after administration to small mammals such as rabbits are often unknown, making safe and effective dose recommendations difficult. Although the safety, efficacy, and pharmacokinetic parameters for numerous pharmaceutical agents have been reported for more traditional domestic animal species, data are needed to ensure proper dosing and treatment of other species for which approved drugs are not available.

Selamectina is a macrocyclic lactone of the avermectin subclass. It is a safe, broad-spectrum endectocide approved for topical use at doses of 6 to 12 mg/kg in cats and dogs.2 Transdermal absorption of selamectin following topical administration in dogs and cats rapidly results in plasma concentrations of the drug, and plasma and tissue concentrations are sustained for several weeks after administration.3 Selamectin is approved for use in killing adult fleas and preventing eggs from hatching for ≥ 1 month in dogs and cats.2 In controlled studies,4 > 98% of fleas were killed within 36 hours after application, and in field studies,5 1 application of selamectin resulted in > 90% reduction in mean flea counts 30 days after administration. Selamectin is also approved for prevention of heartworm disease caused by Dirofilaria immitis and for treatment and control of ear mites (Otodectes cynotis) in dogs and cats. Other approved uses include elimination of roundworm (Toxocara cati) and intestinal hookworm (Ancylostoma tubaeforme) infections in cats, and treatment and control of sarcoptic mange (Sarcoptes scabei) and control of tick infestations caused by Dermacentor variabilis in dogs. In addition, selamectin effectively controls lice6 and Cheyletiella spp7,8 in dogs and cats.

Results of 1 efficacy study9 revealed that topical application of selamectin at a dose of 6 or 18 mg/kg eliminated ear mites (Psoroptes cuniculi) in rabbits. Other reports describing the topical use of selamectin in rabbits indicated that it was effective against P cuniculi and S scabei at doses of 6 to 18 mg/kg,10 S scabei at doses of 8 to 14 mg/kg,11 Cheyletiella parasitovorax at doses of 6.2 to 20 mg/kg (1 to 3 times with an interval of 2 to 4 weeks between treatments)12 or 12 mg/kg (as a single dose),13 and Cheyletiella spp and Leporacaerus gibbus at a dose of 15 mg for rabbits that weighed < 2.3 kg or 45 mg for those that weighed ≥ 2.3 kg.14 Selamectin was recommended for treatment against fleas in rabbits at a dose of 18 mg/kg (repeated 30 days later if needed).15 The extralabel use of this drug for treatment of ectoparasites and some endoparasites in a variety of small mammals (including rabbits) and birds has been reviewed elsewhere.16

Ctenocephalides felis or Ctenocephalides canis (common cat and dog fleas, respectively) are the fleas most typically found on pet rabbits, and these infestations can result from living in shared environments with cats and dogs.17 Infestation causes intense pruritis, and allergic dermatitis can develop. Although no ectoparasiticide is currently licensed for use in rabbits in the United States, selamectin, imidacloprid (flea adulticide), lufenuron (flea ovicide and larvacide), carbaryl powder, and pyrethrins have been used to control fleas in rabbits.17,18 However, to the authors' knowledge, no pharmacokinetic or safety studies of these products have been performed in rabbits.

The objective of the study reported here was to determine pharmacokinetics, efficacy, and adverse effects of selamectin administered topically at doses of 10 or 20 mg/kg in rabbits infested with a predetermined quantity of fleas. We also sought to identify treatment intervals at which these doses of selamectin would maintain effective flea control in rabbits.

Materials and Methods

Animals—Eighteen 5-month-old New Zealand White rabbits (Oryctolagus cuniculus domesticus) with a mean weight of 3.7 kg (range, 3.5 to 4.1 kg) were used in the study. Nine rabbits were males and 9 were females; all were obtained from a commercial supplier and were specific-pathogen (Pasteurella spp) free. Rabbits were housed individually in stainless steel cages, and the cages were grouped according to treatment. No contact was permitted among rabbits or among treatment groups. Rabbits were exposed to cycles of 16 hours of light followed by 8 hours of dark and were fed an alfalfa-based pelleted dietb and timothy hay.c Water was available ad libitum. Immediately prior to the study, rabbits underwent a physical examination that included evaluation of a fecal sample and collection of a blood sample for assessment of Hct and plasma total protein concentration. All rabbits were determined to be healthy, and their behavioral characteristics were assessed as normal. The study was approved by the Institutional Animal Care and Use Committee of Kansas State University.

Experimental design—Rabbits were randomly assigned to 1 of 3 treatment groups, with each group consisting of 6 rabbits (3 males and 3 females) and balanced by weight. Group 1 consisted of untreated controls, and rabbits in groups 2 and 3 were administered selamectina topically in a single spot on the dorsal aspect of the neck at doses of 10 and 20 mg/kg, respectively, on day 0. Assessment for any adverse reactions and evaluation of each rabbit's activity level and food and water consumption were made at 2 and 24 hours after drug administration and once daily thereafter. Weights of the rabbits were measured at the beginning and end of the study.

Efficacy study—On days −1, 7, and 14 (day 0 was the day of selamectin administration), each rabbit was infested with 50 laboratory-raised, unfed fleas (C felis) that had emerged from their pupae within the previous 1 to 4 days. All rabbits were combed for 20 minutes on days 2 (approx 48 hours after drug administration), 9 (approx 48 hours after the first reinfestation), and 16 (approx 48 hours after the second reinfestation). All fleas combed off of each rabbit were placed in a clear plastic bag that was sealed to prevent fleas from escaping. Fleas were then counted and categorized as live or dead (or dying). A flea was categorized as live if it could actively move through hair or could rapidly move into an upright position and readily move or jump when placed on a flat surface. To determine efficacy of the selamectin treatment, flea counts were transformed to the natural logarithm of (count + 1) to calculate geometric means. Percentage efficacy for each treatment group on each day was calculated as follows:

article image

where GMC is geometric mean live flea count of the control group and GMT is geometric mean live flea count of the treated group.

Preparation of plasma samples—A heparinized syringe with a 25-gauge needle was used to collect blood samples (2 mL) from a central ear artery, cephalic vein, or lateral saphenous vein. Samples were collected at time 0 (immediately before topical administration of selamectin) and at 6 and 12 hours and 1, 2, 3, 5, 7, 14, 21, and 28 days after treatment. Plasma was separated via centrifugation (10 minutes at approx 2,000 × g) and stored at −70°C until analyzed.

Selamectin analysis—Selamectin plasma concentrations were determined by use of high-performance liquid chromatographyd with triple-quadrupole mass spectrometry.e Concentrations of selamectin (mass-to-charge ratios, 770.78→113.10, 145.20, 151.10, 203.30, and 276.20) were determined with moxidectin (mass-to-charge ratio, 640.71→528.63) used as the internal standard. Two standard curves were constructed to maintain a linear detector response. The low standard curve for selamectin was constructed by adding selamectin to control (blank) rabbit plasma at concentrations of 0, 5, 10, 20, 40, and 80 ng/mL and was used to measure concentrations from 5 to 80 ng/mL. The high standard curve for selamectin was constructed by adding selamectin to control rabbit plasma at concentrations of 0, 50, 100, 500, 1,000, 2,500 and 5,000 ng/mL and was used to measure concentrations from 50 to 5,000 ng/mL. The standard curves were accepted if measured concentrations were within 15% above or below the actual concentrations and the standard curve was linear with a correlation coefficient of at least 0.99. The LLOQ (5 ng/mL) was defined as the lowest concentration on the standard curve with predicted concentrations within 15% above or below actual concentrations. Accuracy of the analytic assay was 98 ± 11% and 98 ± 10% for the low and high standard curves, respectively. The coefficient of variation was 14% and 5% for the low and high standard curves, respectively.

Plasma samples and standards were prepared by adding 0.05 mL of internal standard (moxidectin [10 μg/mL]) to 0.5 mL of plasma and 0.5 mL of 30% acetonitrile solution. Each plasma mixture was vortexed and then centrifuged for 5 minutes at 15,000 × g. Supernatant was extracted by use of solid-phase extraction cartridgesf that were conditioned with 1 mL of methanol followed by 1 mL of deionized water. Supernatant was added, and the solid-phase extraction cartridges were rinsed with 25% methanol. Samples were eluted with 1 mL of acetonitrile; the eluate was evaporated under an air stream at 40°C and reconstituted with 0.2 mL of a solution of 50% acetonitrile in 0.1% formic acid. Samples were then vortexed and centrifuged at 16,000 × g for 5 minutes for sedimentation of any particulates. The supernatant was transferred to an injection vial, and 50 μL was injected into the high-performance liquid chromatography system. The mobile phase consisted of acetonitrile and a formic acid solution (0.1% formic acid) with a flow rate of 0.3 mL/min. The mobile phase linear gradient started at 40% formic acid solution from 0 to 2 minutes, was changed to a linear gradient to 10% formic acid solution from 2 to 3.5 minutes, and then was changed to a linear gradient to 40% formic acid solution at 4.5 minutes with a 5.5-minute total run time. Separation was achieved with a C8 separation columng at 40°C.

Pharmacokinetic analysis—Non-compartmental pharmacokinetic analysis was performed with computer softwareh for samples with plasma concentrations above the analytic LLOQ. Noncompartmental pharmacokinetic parameters determined included the AUC0–∞ calculated via the linear trapezoidal method, area under the first moment curve, Cl/F, apparent Vd/F, first-order terminal rate constant, T1/2, Cmax, Tmax, and MRT. The AUC0–∞ per dose and Cmax per dose were calculated by dividing the AUC0–∞ and Cmax by the actual dose administered.

Normality of the data was assessed via the Kolmogorov-Smirnov test.i Not all of the pharmacokinetic parameters were normally distributed and of equal variance; therefore, statistical comparisons of pharmacokinetic parameters for selamectin at doses of 10 and 20 mg/kg were compared by use of a Mann-Whitney rank sum test.i Values of P < 0.05 were considered significant.

Results

On day 2 after topical application of selamectin, calculated efficacy for treatment of fleas was 91.3% and 97.1% in rabbits in the 10 and 20 mg/kg treatment groups, respectively (Table 1). On day 9, efficacy had decreased to 37.7% and 74.2% in the 10 and 20 mg/kg treatment groups, respectively. By day 16, efficacy was only 6.6% and 13.5% in the 10 and 20 mg/kg treatment groups, respectively.

Table 1—

Geometric mean* adult live flea counts (efficacy [%]) following 1 dose of selamectin (10 or 20 mg/kg) administered topically in healthy New Zealand White rabbits (n = 6/group).

DayUntreated control10 mg/kg20 mg/kg
217.27a1.5b (91.31)0.5b (97.10)
922.52a14.03a (37.70)5.8b (74.24)
1621.30a19.89a (6.62)18.42a (13.52)

Rabbits were infested with 50 cat fleas on days −1, 7, and 14, and combed for 20 minutes on days 2, 9, and 16 (the day of drug administration was considered day 0). Fleas were collected into plastic bags and counted. Percentage efficacy was calculated as (GMC − GMT × 100)/GMC, where GMC is geometric mean live flea count of the control group and GMT is geometric mean live flea count of the treated group.

Back transformation of least squares means from the natural logarithm of (count + 1) to geometric mean.

Values across rows with different superscripts are significantly (P ≤ 0.05) different.

Plasma concentrations of selamectin in rabbits after transdermal absorption of the topically applied drug were graphed (Figure 1). Selamectin concentrations above the analytic LLOQ were not detected in any samples collected after day 7. Mean Cmax values for selamectin were 91.7 ng/mL in the 10 mg/kg dose group and 304.2 ng/mL in the 20 mg/kg dose group; these values were significantly (P = 0.041) different between the 2 groups (Table 2). However, the mean Cmax per dose was not significantly (P = 0.240) different between the 10 and 20 mg/kg dose groups (9.2 and 15.2 ng/mL, respectively). Mean AUC0–∞ was not significantly (P = 0.093) different between the 10 and 20 mg/kg dose groups (140.4 and 432.0 d•ng/mL, respectively). Similarly, mean AUC0–∞ per dose was not significantly (P = 0.203) different between the 10 and 20 mg/kg dose groups (14.04 and 21.60 d•ng/mL, respectively). The T1/2, MRT, Tmax, apparent Vd/F, and Cl/F were not significantly different between the 2 treatment groups. On the basis of clinical observations, no detectable adverse reactions developed in rabbits of either treatment group at any time point.

Figure 1—
Figure 1—

Mean ± SD plasma selamectin concentrations in healthy New Zealand White rabbits after topical administration of 1 dose of selamectin at 10 (black circles; n = 6) or 20 (white circles; 6) mg/kg. Numbers in parentheses indicate the number of samples with selamectin concentrations above the LLOQ of the analytic assay (5 ng/mL) if < 6 samples/time point. The day of drug administration was considered day 0.

Citation: American Journal of Veterinary Research 73, 4; 10.2460/ajvr.73.4.562

Table 2—

Mean and range of pharmacokinetic parameters for selamectin after topical administration of a single dose of selamectin at 10 or 20 mg/kg in rabbits (n = 6/group).

 10 mg/kg20 mg/kg 
ParameterMeanRangeMeanRangeP value
AUCextrapolated (%)8.33.8–14.83.60.9–10.40.132
AUC0–∞/dose (d·ng/mL)14.046.07–32.8621.607.84–32.630.203
AUC0–∞(d·ng/mL)140.460.7–328.6432.0156.8–652.60.093
AUMC (d·ng/mL)218.5101.1–422.6766.6408.0–1,140.90.004
Cl/F (mL/min/kg)49.521.1–114.432.221.3–88.60.240
Cmax (ng/mL)91.730.2–278.0304.266.4–531.00.041
Cmax/dose (ng/mL)9.23.0–27.815.23.3–26.60.240
T1/2 (d)0.930.58–1.700.970.21–2.210.485
λz (1/d)0.7450.407–1.2000.7140.313–3.2560.485
MRT (d)1.61.1–2.31.80.9–2.90.240
Tmax (d)0.450.25–1.000.500.25–2.001.000
Apparent Vd/F (L/kg)95.625.4–228.264.812.5–407.40.485

AUCextrapolated = Percentage of the area under the plasma concentration curve extrapolated to infinity. AUMC = Area under the first moment curve. λz = First-order terminal rate constant.

Discussion

In the study reported here, pharmacokinetics, efficacy, and adverse effects of topically administered selamectin (6% wt/vol; 10 or 20 mg/kg, administered once) were assessed in healthy rabbits. No significant differences were detected in T1/2, Tmax, AUC0–∞ per dose, or Cmax per dose between the 2 dose groups. This lack of differences could be attributable to one of the following: a true difference was not present; a true difference was present, but variability was too great to result in a significant difference; or a true difference was present, but the study design and data analyses did not allow detection of the difference. Extrapolations of these pharmacokinetic parameters beyond 10 to 20 mg/kg may not be accurate and should be made cautiously.

The pharmacokinetics of selamectin were previously evaluated in cats and dogs following topical administration at a dose of 24 mg/kg.3 Mean Cmax in cats and dogs was 5,513 ± 2,173 ng/mL and 86.5 ± 34.0 ng/mL, respectively. The reported Cmax of selamectin in cats was much greater than that achieved in the rabbits of the present study that received a 20 mg/kg dose (mean, 304.2 ng/mL), but Cmax in these rabbits was much greater than that described in dogs of the previous study.3 The T1/2 of selamectin after topical administration in cats and dogs was 8.3 and 11.1 days,3 respectively, which was much longer than that in the rabbits of the present study administered 20 mg/kg topically (0.97 days).

Although selamectin at doses of 10 or 20 mg/kg was ≥ 91.3% effective against existing flea infestations on rabbits 2 days after application, it did not provide prolonged residual activity. On the basis of results of our pharmacokinetic analysis, drug exposure was increased when the dose was increased; however, only 2 doses were assessed. Further increases in the dose of selamectin may result in greater plasma concentrations in rabbits and subsequently longer duration of effects but may also increase the risk of adverse effects. The short duration of efficacy of selamectin was most likely due to the short T1/2 after topical administration in rabbits (0.93 to 0.97 days), compared with 8.3 days in cats and 11.1 days in dogs.3 However, the reported elimination half-lives of selamectin after IV administration in dogs and cats were 0.6 and 2.9 days, respectively, suggesting that a delayed absorption phase occurs following topical administration in dogs and cats (ie, a flip-flop phenomenon). In a flip-flop phenomenon, the terminal portion of the plasma profile after non-IV drug administration is influenced by the absorption rate being much slower than the elimination rate; subsequently, absorption is the rate-limiting phase that controls the T1/2. Because of selamectin was not administered IV to rabbits in the present study to determine the true elimination half-life, it is unknown whether a flip-flop phenomenon also occurs in rabbits. The short T1/2 in rabbits suggests that the duration of effect would be shorter in rabbits, compared with that in dogs and cats, if the plasma drug concentrations are directly correlated with the drug effect.

A compartmental pharmacokinetic model could not be fit to the data in the present study because of the study design. The inability to fit a compartmental model was attributed to the rapid absorption and elimination of selamectin and the LLOQ of the analytic assay. Therefore, a noncompartmental pharmacokinetic method was used. More frequent sample collection between days 0 to 7 may have resulted in enough data points to fit a compartmental model; however, it was not anticipated that selamectin would be eliminated at the rapid rate detected. Future studies should include more intensive sampling from days 0 to 7 to fit a compartmental model to the data.

Although no safety studies in rabbits have been reported, topically administered selamectin at doses of 6 to 12 mg/kg were shown to be safe in cats and dogs,19,20 with adverse reactions rarely reported.2 In the present study, no clinical signs indicative of adverse effects associated with selamectin were detected in rabbits after a single dose of 10 or 20 mg/kg.

The rabbits in the present study absorbed selamectin transdermally much more rapidly than was reported for cats or dogs.3 This finding indicates that veterinarians must be very careful in extrapolating dosages of topically administered drugs described for dogs and cats to species in which use is not approved because overdoses and toxicosis could potentially result.

Based on the efficacy and pharmacokinetic findings in the present study, topical administration of selamectin at a dosage of 20 mg/kg every 7 days is efficacious for the treatment of flea infestations in rabbits. However, further studies on the safety, pharmacokinetics, and pharmacodynamics of multiple doses and topical applications repeated weekly need to be completed prior to routine use of selamectin in this species.

ABBREVIATIONS

AUC0−∞

Area under the plasma concentration-versus-time curve from time 0 through infinity

Cl

Plasma clearance

Cmax

Maximum plasma concentration

F

Fraction of absorbed dose

LLOQ

Lower limit of quantification

MRT

Mean residence time

T1/2

Terminal half-life

Tmax

Time to reach maximum plasma concentration

Vd

Volume of distribution determined by use of the area method

a.

Revolution, Pfizer Animal Health, New York, NY.

b.

Bunny basics 15/23, Oxbow Pet Products, Murdock, Neb.

c.

Western Timothy Hay, Oxbow Pet Products, Murdock, Neb.

d.

Shimadzu Prominence, Shimadzu Scientific Instruments, Columbia, Md.

e.

API 2000, Applied Biosystems, Foster City, Calif.

f.

Bond Elut C18, Varian, Palo Alto, Calif.

g.

Supelco Discovery, 50 × 2.1 mm, 5 μm, Sigma-Aldrich, St Louis, Mo.

h.

WinNonlin 5.2, Pharsight Corp, Mountain View, Calif.

i.

SigmaStat, version 3.11, Systat Software Inc, San Jose, Calif.

References

  • 1.

    AVMA. U.S. pet ownership & demographics sourcebook. Schaumburg, Ill: AVMA, 2007;1159.

  • 2.

    Revolution [package insert]. Exton, Pa: Pfizer Animal Health, 2011.

  • 3.

    Sarasola P, Jernigan AD, Walker DK, et al. Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs. J Vet Pharmacol Ther 2002; 25:265272.

    • Search Google Scholar
    • Export Citation
  • 4.

    McTier TL, Shanks DJ, Jernigan AD, et al. Evaluation of the effects of selamectin against adult and immature stages of fleas (Ctenocephalides felis felis) on dogs and cats. Vet Parasitol 2000; 91:201212.

    • Search Google Scholar
    • Export Citation
  • 5.

    Boy MG, Six RH, Thomas CA, et al. Efficacy and safety of selamectin against fleas and heartworms in dogs and cats presented as veterinary patients in North America. Vet Parasitol 2000; 91:233250.

    • Search Google Scholar
    • Export Citation
  • 6.

    Shanks DJ, Gautier P, McTier TL, et al. Efficacy of selamectin against biting lice on dogs and cats. Vet Rec 2003; 152:234237.

  • 7.

    Chailleux N & Paradis M. Efficacy of selamectin in the treatment of naturally acquired cheyletiellosis in cats. Can Vet J 2002; 43:767770.

    • Search Google Scholar
    • Export Citation
  • 8.

    Mueller RS, Bettenay SV. Efficacy of selamectin in the treatment of canine cheyletiellosis. Vet Rec 2002; 151:773.

  • 9.

    McTier TL, Hair JA, Walstrom DJ, et al. Efficacy and safety of topical administration of selamectin for treatment of ear mite infestation in rabbits. J Am Vet Med Assoc 2003; 223:322324.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kurtdede A, Karaer Z, Acar A, et al. Use of selamectin for the treatment of psoroptic and sarcoptic mite infestation in rabbits. Vet Dermatol 2007; 18:1822.

    • Search Google Scholar
    • Export Citation
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    Farmaki R, Koutinas AF, Papazahariadou MG, et al. Effectiveness of a selamectin spot-on formulation in rabbits with sarcoptic mange. Vet Rec 2009; 164:431432.

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Contributor Notes

Supported by a grant from Pfizer Animal Health.

Presented in abstract form at the Annual Conference of Avian Veterinarians, San Diego, August 2010.

Address correspondence to Dr. Carpenter (carpentr@vet.ksu.edu).