Seizures are the most common neurologic disorder of dogs, and idiopathic epilepsy is the most common cause of chronic, recurring seizures.1 If untreated, seizures can result in substantial illness and death. Aside from the physical ramifications of seizures in affected dogs, recurrent seizures are a source of emotional stress and financial strain for their owners. Consequently, the goal for the treatment of affected dogs is to reduce seizure severity and frequency. There are multiple treatment options; however, not all patients respond to the most commonly used drugs, and many of those drugs have undesirable adverse effects.
Zonisamide is a sulfonamide anticonvulsant with several likely mechanisms of action including modulation of the dopaminergic and serotonergic systems, binding to γ-aminobutyric acid chloride channels, inhibition of glutamate release, and blockage of t-type calcium and voltage-gated sodium channels.2–4 Zonisamide is most commonly used as an adjunctive maintenance therapy for dogs with refractory idiopathic epilepsy. Results of 2 prospective open-label studies2,3 indicate that the addition of zonisamide to the treatment regimen (ie, phenobarbital or potassium bromide) of dogs with recurrent seizures decreases seizure frequency, and for some dogs, the addition of zonisamide to the treatment regimen made it possible to decrease the dosage of the first-line anti-seizure medication, thus reducing the adverse effects associated with that medication and decreasing the treatment cost for the owners. Oral administration of zonisamide has also been used as the first-line treatment or monotherapy for dogs with idiopathic epilepsy. In another prospective open-label study,5 6 of 10 dogs with idiopathic epilepsy that were treated with zonisamide (5 to 10 mg/kg, PO, q 12 h) monotherapy had a ≥ 50% decrease in the monthly frequency of seizures.
Adverse effects associated with zonisamide administration in dogs are typically minor and transient and include mild sedation, ataxia, and vomiting.1,2,5 Zonisamide is metabolized primarily by hepatic micro-somal enzymes, and a mild increase in alkaline phosphatase activity is possible with chronic administration.2,6 Erythema multiforme7 and apparent idiosyncratic hepatic necrosis8,9 have been reported in 1 and 2 dogs, respectively, and were most likely attributable to sulfonamide hypersensitivity. Zonisamide administration was associated with renal tubular acidosis in 1 dog,10 which might have been the result of zonisamide-induced inhibition of carbonic anhydrase.4,10
In the United States, zonisamide is currently commercially available only as an encapsulated powder for oral administration. Investigators of previous pharmacokinetic studies4,11–13 produced and used an injectable zonisamide solution. However, because that formulation is not commercially available, zonisamide powder has anecdotally been administered per rectum to dogs that are too sedate or ill from adverse effects of other drugs or neurologic or systemic disease to safely swallow medication. This practice was extrapolated and adopted on the basis of data that suggest therapeutic target plasma concentrations of zonisamide are achieved in rodents following administration of zonisamide suppositories.12 The published literature contains only sparse pharmacological data regarding rectal administration of zonisamide to dogs. Results of 1 study14 indicate that the plasma zonisamide concentration of dogs following rectal administration of zonisamide (10 mg/kg) dissolved in water or as a suppository after being compounded with PEG was significantly lower than that achieved following oral administration of the same dose of the drug. The empirical dose of zonisamide (30 mg/kg) that is commonly used for rectal administration was extrapolated on the basis of the results of that study14 and the study12 performed in rodents. Objective data regarding the pharmacokinetics of zonisamide following rectal administration to dogs are lacking; therefore, the appropriate dose of zonisamide for rectal administration to dogs is unknown.
The purpose of the study reported here was to determine the pharmacokinetics of zonisamide in healthy dogs following rectal administration of each of 2 doses (20 and 30 mg/kg) suspended in sterile water or PEG. Our goals were to use that information to determine the optimal drug delivery substrate (water or PEG) and recommend an appropriate dose of zonisamide for rectal administration to dogs. We hypothesized that rectal administration of commercially available zonisamide powder suspended in water or PEG at doses of 20 and 30 mg/kg would result in plasma zonisamide concentrations within the recommended therapeutic target range (10 to 40 μg/mL) and that the Cmax following administration of zonisamide suspended in PEG would be greater than that following administration of zonisamide suspended in sterile water. Finally, we compared the pharmacokinetics of zonisamide following rectal administration as determined in this study to those following oral administration as determined in previous studies4,11,14 to determine whether rectal administration might be an appropriate substitute route of zonisamide administration for dogs in which oral administration of medications is contraindicated.
Supported by grants from the American College of Veterinary Internal Medicine and the University of Tennessee College of Veterinary Medicine Companion Animal Fund.
Presented as an oral presentation at the 2015 American College of Veterinary Internal Medicine Forum, Indianapolis, June 2015.
The authors thank Tamberlyn Moyer for technical assistance and Xiaocun Sun for assistance with statistical analysis.
Area under the concentration-time curve from time 0 to infinity
Maximum plasma concentration
High-performance liquid chromatography
Mean residence time from time 0 to infinity
Time to maximum plasma concentration
Zonisamide 100-mg capsules, Mylan, Canonsburg, Penn.
Monoject lithium heparin tubes, Fisher Scientific, Itasca, Ill.
WinNonLin, Pharsight Corp, Mountain View, Calif.
SSPS Statistics for Windows, verion 2.0, IBM Corp, Armonk, NY.
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