Pharmacokinetics and safety of zonisamide after oral administration of single and multiple doses to Hispaniolan Amazon parrots (Amazona ventralis)

Krista A. Keller William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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David Sanchez-Migallon Guzman Departments of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Dawn M. Boothe Department of Anatomy, Physiology and Pharmacology and Clinical Pharmacology Laboratory, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

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Marike Visser Department of Anatomy, Physiology and Pharmacology and Clinical Pharmacology Laboratory, College of Veterinary Medicine, Auburn University, Auburn, AL 36849.

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Ricardo E. de Matos Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Olivia A. Petritz William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Philip H. Kass Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Joanne R. Paul-Murphy Departments of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

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Abstract

OBJECTIVE To determine pharmacokinetics after oral administration of single and multiple doses and to assess the safety of zonisamide in Hispaniolan Amazon parrots (Amazona ventralis).

ANIMALS 12 adult Hispaniolan Amazon parrots.

PROCEDURES Zonisamide (30 mg/kg, PO) was administered once to 6 parrots in a single-dose trial. Six months later, a multiple-dose trial was performed in which 8 parrots received zonisamide (20 mg/kg, PO, q 12 h for 10 days) and 4 parrots served as control birds. Safety was assessed through monitoring of body weight, attitude, and urofeces and comparison of those variables and results of CBC and biochemical analyses between control and treatment groups.

RESULTS Mean ± SD maximum plasma concentration of zonisamide for the single- and multiple-dose trials was 21.19 ± 3.42 μg/mL at 4.75 hours and 25.11 ± 1.81 μg/mL at 2.25 hours after administration, respectively. Mean plasma elimination half-life for the single- and multiple-dose trials was 13.34 ± 2.10 hours and 9.76 ± 0.93 hours, respectively. Pharmacokinetic values supported accumulation in the multiple-dose trial. There were no significant differences in body weight, appearance of urofeces, or appetite between treated and control birds. Although treated birds had several significant differences in hematologic and biochemical variables, all variables remained within reference values for this species.

CONCLUSIONS AND CLINICAL RELEVANCE Twice-daily oral administration of zonisamide to Hispaniolan Amazon parrots resulted in plasma concentrations known to be therapeutic in dogs without evidence of adverse effects on body weight, attitude, and urofeces or clinically relevant changes to hematologic and biochemical variables.

Abstract

OBJECTIVE To determine pharmacokinetics after oral administration of single and multiple doses and to assess the safety of zonisamide in Hispaniolan Amazon parrots (Amazona ventralis).

ANIMALS 12 adult Hispaniolan Amazon parrots.

PROCEDURES Zonisamide (30 mg/kg, PO) was administered once to 6 parrots in a single-dose trial. Six months later, a multiple-dose trial was performed in which 8 parrots received zonisamide (20 mg/kg, PO, q 12 h for 10 days) and 4 parrots served as control birds. Safety was assessed through monitoring of body weight, attitude, and urofeces and comparison of those variables and results of CBC and biochemical analyses between control and treatment groups.

RESULTS Mean ± SD maximum plasma concentration of zonisamide for the single- and multiple-dose trials was 21.19 ± 3.42 μg/mL at 4.75 hours and 25.11 ± 1.81 μg/mL at 2.25 hours after administration, respectively. Mean plasma elimination half-life for the single- and multiple-dose trials was 13.34 ± 2.10 hours and 9.76 ± 0.93 hours, respectively. Pharmacokinetic values supported accumulation in the multiple-dose trial. There were no significant differences in body weight, appearance of urofeces, or appetite between treated and control birds. Although treated birds had several significant differences in hematologic and biochemical variables, all variables remained within reference values for this species.

CONCLUSIONS AND CLINICAL RELEVANCE Twice-daily oral administration of zonisamide to Hispaniolan Amazon parrots resulted in plasma concentrations known to be therapeutic in dogs without evidence of adverse effects on body weight, attitude, and urofeces or clinically relevant changes to hematologic and biochemical variables.

Doses of AEDs in companion avian species are often extrapolated from published safe and effective doses used in nonavian species or derived from case reports of a single bird.1 Pharmacokinetic studies of AEDs have been limited to administration of gabapentin in great horned owls (Bubo virginianus)2 and Hispaniolan Amazon parrots (Amazona ventralis),3 levetiracetam in Hispaniolan Amazon parrots,4 phenobarbital in Congo African grey parrots (Psittacus erithacus erithacus),5 and a variety of AEDs (ethosuximide, phenytoin, phenobarbital, primidone, and zonisamide) in chickens.6–9,a These studies highlight differences between avian species and other companion mammals that make it challenging to accurately extrapolate dosages for birds from data for companion mammal species.

Zonisamide, a sulfonamide-derivative AED, is thought to have multiple mechanisms by which it prevents seizure activity, including modulation of ion channels, enhancement of neurotransmitters, and inhibition of carbonic anhydrase.10,11 Studies have found zonisamide to be effective and safe when used alone or as adjuvant therapy for treatment of epilepsy in humans11–13 and dogs.14–16 Zonisamide has been anecdotally used in psittacine species,1 and a pharmacokinetic and safety evaluation has been performed for chickens.a Plasma concentrations known to have anticonvulsant activity in humans10,12 and dogs14 (10 to 40 μg/mL) were reached in chickens after administration of zonisamide (20 mg/kg, PO); however, dose-dependent diarrhea developed, and one-fourth of the chickens developed immune-mediated hemolytic anemia and acute severe hepatic necrosis.a

The goals of the study reported here were to determine the pharmacokinetics of zonisamide after oral administration of single and multiple doses to Hispaniolan Amazon parrots and to assess safety of zonisamide during oral administration for 10 days. We hypothesized that zonisamide administered at a dosage of 20 mg/kg, PO, every 12 hours would yield plasma concentrations known to inhibit seizures in dogs and that this dose would be safe during the 10-day period.

Materials and Methods

Animals

Twelve adult Hispaniolan Amazon parrots that were part of a research colony at the University of California-Davis School of Veterinary Medicine were used in the study, which consisted of single- and multiple-dose trials. Prior to the study, the birds were housed in a group flight cage (3.66 × 2.74 × 2.13 m). Birds were housed in a single room in individual stainless-steel cages or in hanging-wire cages (60.96 × 58.42 × 66.04 cm) for 3 days prior to venipuncture at the start of the study. The diet included a commercially pelleted feed,b and water was provided ad libitum via a sipper bottle. Parrots were healthy as determined on the basis of the medical history and results of a physical examination. The birds had been used in other studies, including a study evaluating bone marrow aspirates of the tibiotarsus conducted 3 months prior to the study reported here. None of the birds had received medications or anesthetics for at least 1 month prior to sample collection in the present study. The study protocol was approved by the Institutional Animal Care and Use Committee at the University of California-Davis (No. 16548).

Preparation of suspensions

Zonisamide was prepared as a 10-mg/mL suspension. This suspension is stable at room temperature (approx 23°C) for up to 28 days.17 Contents of two 100-mg capsules of zonisamidec were mixed into 20 mL of a flavored syrup vehicled and 20 mL of an oral suspending vehiclee to create the final zonisamide suspension. A control suspension of the flavored syrup vehicle and oral suspending vehicle (ratio, 1:1) without zonisamide was prepared for the multiple-dose trial.

Single-dose trial

Six adult Hispaniolan Amazon parrots (3 males and 3 females) were used in the single-dose trial. Body weight of the parrots ranged from 0.27 to 0.32 kg. Each bird received a single dose of zonisamide (30 mg/kg) administered into the crop with a metal gavage tube. Investigators flushed the gavage tube with air to ensure that it was completely evacuated of drug. Mean volume of zonisamide suspension administered was 0.89 mL (range, 0.82 to 0.96 mL).

A baseline blood sample (0.25 to 0.30 mL) was collected 1 week prior to zonisamide administration. Blood samples also were collected 0.5, 1, 2, 3, 4, 8, 12, 24, and 36 hours after zonisamide administration.

Multiple-dose trial

Twelve adult Hispaniolan Amazon parrots (6 males and 6 females; 6 of these birds participated in the single-dose trial) were used in a multiple-dose trial, which was conducted 6 months after the end of the single-dose trial. Initial body weight ranged from 0.27 to 0.35 kg. Birds were allocated into 2 groups by randomly drawing an assignment card (control vs treatment) from a hat for each bird. Eight birds received zonisamide suspension (20 mg/kg, PO, q 12 h for 10 days), and 4 birds received the control suspension twice daily at the same volume calculated for the zonisamide suspension. A lower dose of zonisamide was selected for the multiple-dose trial after analysis of data for the single-dose trial and because of concerns about accumulation and potential toxicoses with a longer treatment period. Mean volume of zonisamide or control suspension administered was 0.59 mL (range, 0.49 to 0.73 mL). Both suspensions were administered into the crop of birds by use of a metal gavage tube.

Before birds were handled each day, they were observed in their cages, and overall attitude was assessed. Photographs of the urofeces were obtained immediately before and after suspension administration. Body weight of each bird was measured each morning prior to solution administration.

Before the administration of zonisamide or control suspension on the morning of days 1, 3, and 10, a blood sample was collected from each of the 12 birds for a CBC and plasma biochemical analysis. Blood samples were obtained on days 1 and 3 at 5 and 12 hours after administration of the morning dose and used for quantitation of plasma zonisamide concentrations. The 5-hour time point was selected on the basis of data from the single-dose trial. Furthermore, on the last day of administration (day 10), zonisamide was administered only in the morning, and blood samples were collected immediately before and 1, 2, 3, 5, 8, 12, 24, and 36 hours after administration of that dose.

Blood collection

All blood samples were collected from the right or left jugular vein with a 26-gauge needle and 1-mL syringe. Birds were manually restrained during blood collection. Blood was transferred directly from the syringe into an Hct tube, and 1 or 2 blood films were made on glass slides. The remaining portion of each blood sample was transferred to lithium-heparin pediatric collection tubesf and refrigerated. Samples were centrifuged (3,500 × g for 6 minutes) within 1 hour after collection. Plasma was harvested and processed for biochemical analysis or placed into labeled 0.5-mL cryovialsg and stored at −20°C until assayed.

Sample analysis

The CBC and plasma biochemical analysis were performed at the University of California-Davis Veterinary Medical Teaching Hospital. A PCV was obtained by use of a microhematocrit tube and centrifugation. Blood films were stained with Romanowsky stain via an automatic slide stainerh and then counterstained with Giemsa stain.i A 200-cell differential count and WBC count by use of Natt-Herrick stainj (modified by the addition of 0.5% new methylene blue staink) and a hemacytometerl were manually performed on all samples by the same technologist. Thrombocytes in the blood films were subjectively assessed as decreased in number, adequate, or increased in number.

Plasma samples were analyzed with a commercially available analyzer.m The clinical biochemical profile included evaluation of concentrations of albumin, bicarbonate, BUN, calcium, chloride, cholesterol, globulin, glucose, phosphorus, potassium, sodium, total protein, and uric acid; the anion gap; and activities of alkaline phosphatase, aspartate aminotransferase, creatine kinase, and glutamate dehydrogenase.

Samples were shipped on dry ice to the Clinical Pharmacology Laboratory at Auburn University for analysis of the plasma concentration of zonisamide. For analysis, samples were thawed at room temperature and mixed to ensure homogeneity. Zonisamide was detected in plasma by use of a diagnostic kitn on a general chemistry analyzer.o The upper limit of quantitation was 80 μg/mL, and the lower limit of quantitation was 2 μg/mL. Samples with a concentration at the upper limit were diluted, which provided an upper limit of 120 μg/mL for samples that had to be diluted. Commercially available calibrationp and diagnosticq kits were used for calibration and quality control purposes.

Data analysis

Data for zonisamide concentration versus time in the single-dose trial and for samples obtained after the last dose in the multiple-dose trial were subjected to noncompartmental linear regression analysis by use of the log-linear rule for determination.r Pharmacokinetic parameters determined included the AUC (extrapolated from time 0 to infinity by use of the trapezoidal and log-linear methods), Cmax, Tmax, MRT, and t1/2 (based on regression analysis of the terminal component of the elimination curve). Relative bioavailability after multiple administrations was determined by use of the following equation:

article image

where AUCmultiple and AUCsingle are the AUC (extrapolated from time 0 to infinity) for the multiple- and single-dose trials, respectively, and dosesingle and dosemultiple are the dose administered for the single- and multiple-dose trials, respectively. Mean absorption time, plasma clearance, and apparent volume of distribution could not be determined because zonisamide was not administered IV.

Statistical analysis

Mean, SD, and 95% confidence interval were reported for all variables, except for t1/2, which was reported as harmonic mean and pseudo-SD. Mixed-effects linear regression with commercially available softwares was used to evaluate the main effects of treatment and the time-by-treatment interaction on body weight, CBC results, and biochemical variables for the zonisamide-treated birds, compared with those for the control group. Values of P ≤ 0.05 were considered significant.

Results

During both the single- and multiple-dose trials, none of the birds exhibited clinical signs associated with toxicoses. All birds remained bright and responsive, had a normal appetite, and maintained body weight throughout the study. Urofeces were subjectively assessed as unchanged during the multiple-dose trial.

Concentration-time curves were plotted for the single- and multiple-dose trials (Figure 1). Pharmacokinetic parameters were determined for both trials (Table 1). In both trials, mean zonisamide concentration remained within the reported therapeutic range of 10 to 40 μg/mL for humans and dogs10,12,14 for at least 12 hours. At 12 hours after administration on day 10 of the multiple-dose trial, all parrots had plasma concentrations > 10 μg/mL, except for 1 parrot that had a concentration of 9.6 μg/mL. In comparison to results for the single-dose trial (30 mg/kg, once), results for the multiple-dose trial (20 mg/kg, every 12 hours for 10 days) included lower values for t1/2, MRT, and Tmax and a higher Cmax. Relative bioavailability for the multiple-dose trial, compared with that for the single-dose trial, was 1.25.

Table 1—

Mean ± SD (95% confidence interval) for pharmacokinetic variables of 6 Hispaniolan Amazon parrots (Amazona ventralis) that received a single dose of zonisamide (30 mg/kg, PO) and 8 Hispaniolan Amazon parrots that received twice-daily doses of zonisamide (20 mg/kg, PO, q 12 h for 10 days).

VariableSingle-dose trialMultiple-dose trial
AUC0–∞ (μg•h/mL)502.91 ± 100.25 (419.10–586.73)419.72 ± 60.29 (369.32–470.12)
Cmax (μg/mL)21.19 ± 3.42 (18.32–24.05)25.11 ± 1.81 (23.60–26.62)
t1/2 (h)*13.34 ± 2.10 (11.84–15.43)9.76 ± 0.93 (8.99–10.53)
MRT (h)21.12 ± 3.71 (18.02–24.22)13.81 ± 1.32 (12.71–14.91)
Tmax (h)4.75 ± 2.06 (3.03–6.47)2.25 ± 0.71 (1.66–2.84)

Value reported is harmonic mean ± pseudo-SD (95% confdence interval).

AUC0–∞ = The AUC extrapolated from time 0 to infinity.

Figure 1—
Figure 1—

Mean ± SD plasma concentration of zonisamide in samples obtained from Hispaniolan Amazon parrots (Amazona ventralis) after oral administration of a single dose of zonisamide (30 mg/kg) to 6 parrots (A) and after oral administration of multiple doses of zonisamide (20 mg/kg every 12 hours for 10 days) to 8 parrots (B) on days 1 (first day of administration; black circles) and 10 (white circles). Time 0 was the time of zonisamide administration for the single-dose trial and time of administration of the last dose on day 10 for the multiple-dose trial.

Citation: American Journal of Veterinary Research 80, 2; 10.2460/ajvr.80.2.195

Birds receiving zonisamide and control birds did not differ significantly with regard to body weight; number of WBCs, heterophils, lymphocytes, basophils, and monocytes; concentrations of albumin, BUN, cholesterol, globulin, glucose, phosphorus, total protein, and uric acid; and activities of alkaline phosphatase, aspartate aminotransferase, creatine kinase, and glutamate dehydrogenase (Table 2). There was a significant difference in PCV (P = 0.038), number of eosinophils (P = 0.032), and concentrations of calcium (P = 0.013), chloride (P < 0.001), potassium (P = 0.023), sodium (P < 0.001), and bile acids (P = 0.013) between the zonisamide-treated and control birds, when controlling for time. No significant interaction between treatment and time was detected.

Table 2—

Mean ± SD (range) values for hematologic and plasma biochemical variables for samples obtained on days 3 and 10 from 8 Hispaniolan Amazon parrots that received twice-daily doses of zonisamide (30 mg/kg, PO, q 12 h for 10 days) and 4 Hispaniolan Amazon parrots that received twice-daily doses of a vehicle control suspension for 10 days.

 Day 3Day 10 
VariableZonisamideControlZonisamideControlP value*
PCV (%)45.8 ± 2.3 (43.5–50.5)47.3 ± 2.9 (44.0–51.0)48.1 ± 3.2 (44.0–53.0)51.5 ± 2.0 (49.5–53.5)0.038
WBCs (X 103 cells/mL)10.3 ± 0.96 (8.2–11.2)10.5 ± 1.55 (8.4–12.0)11.1 ± 2.42 (7.2–14.0)11.1 ± 1.6 (8.8–12.2)0.904
Heterophils (%)55.0 ± 12.4(34.0–73.0)52.0 ± 6.7 (44.0–58.0)50.8 ± 6.5 (45.0–65.0)49.3 ± 6.1 (43.0–57.0)0.695
Lymphocytes (%)42.1 ± 12.2 (24.0–62.0)46.0 ± 7.4 (39.0–55.0)47.3 ± 6.6 (34.0–54.0)50.3 ± 6.4 (43.0–57.0)0.495
Monocytes (%)0 (0)0.3 ± 0.5 (0–1.0)0 (0)0 (0)0.121
Eosinophils (%)2.3 ± 1.0 (1.0–4.0)1.3 ± 0.5 (1.0–2.0)1.0 ± 1.1 (0–3.0)0.5 ± 1.0 (0–2.0)0.032
Basophils (%)0.6 ± 0.7 (0–2.0)0.5 ± 0.6 (0–1.0)1.0 ± 1.1 (0–3.0)0 (0)0.088
Na (mmol/L)151.4 ± 2.1 (149.0–155.0)155.8 ± 1.5 (154.0–157.0)153.0 ± 1.6 (151.0–156.0)155.0 ± 1.8 (153.0–157.0)< 0.001
K (mmol/L)3.1 ± 0.9 (1.9–4.5)2.8 ± 0.9 (1.9–3.8)3.2 ± 0.4 (2.5–3.7)2.2 ± 0.2 (1.9–2.3)0.023
Cl (mmol/L)117.4 ± 1.2 (115.0–119.0)115.5 ± 1.9 (114.0–118.0)121.5 ± 2.3 (118.0–125.0)114.0 ± 1.8 (112.0–116.0)< 0.001
P (mg/dL)3.7 ± 0.3 (3.3–4.1)3.5 ± 1.1 (2.4–5.0)3.8 ± 0.4 (3.3–4.3)3.2 ± 0.4 (2.6–3.6)0.067
Ca (mg/dL)9.7 ± 0.4 (9.2–10.4)10.2 ± 0.3 (9.8–10.5)9.8 ± 0.5 (9.1–10.5)10.5 ± 0.2 (10.2–10.7)0.013
BUN (mg/dL)1.8 ± 0.5 (1.0–2.0)1.3 ± 0.5 (1.0–2.0)2.0 ± 0 (2.0–2.0)2.0 ± 0 (2.0–2.0)0.078
Glucose (mg/dL)278.4 ± 10.6 (263.0–296.0)285.0 ± 16.2 (271.0–304.0)271.9 ± 7.9 (264.0–288.0)280.3 ± 16.0 (264.0–294.0)0.189
Total protein (g/dL)3.8 ± 0.4 (3.2–4.3)3.7 ± 0.3 (3.4–4.0)3.7 ± 0.3 (3.3–4.1)3.9 ± 0.1 (3.7–4.0)0.586
Albumin (g/dL)1.8 ± 0.2 (1.6–2.0)1.8 ± 0.1 (1.6–1.8)1.8 ± 0.1 (1.6–2.0)1.9 ± 0.1 (1.8–2.0)0.559
Globulin (g/dL)2.0 ± 0.2 (1.6–2.3)1.9 ± 0.2 (1.7–2.2)1.9 ± 0.2 (1.5–2.2)2.0 ± 0.1 (1.8–2.0)0.633
AST (U/L)400.9 ± 216.2 (247.0–897.0)426.0 ± 125.4 (338.0–612.0)304.6 ± 84.7 (236.0–487.0)296.5 ± 65.9 (227.0–386.0)0.909
CK (U/L)967.1 ± 703.0 (377.0–2,366.0)509.0 ± 113.4 (353.0–602.0)462.5 ± 234.3(206.0–890.0)211.5 ± 65.9 (227.0–386.0)0.085
ALP (U/L)42.6 ± 14.5 (29.0–70.0)30.0 ± 14.5 (17.0–50.0)63.4 ± 24.4 (30.0–101.0)41.0 ± 23.9 (19.0–73.0)0.094
GDH (U/L)1.1 ± 1.6 (0–4.0)2.8 ± 2.4 (1.0–6.0)1.4 ± 1.3 (0–3.0)1.5 ± 1.3 (0–3.0)0.299
Cholesterol (mg/dL)396.4 ± 37.7 (349.0–441.0)377.0 ± 30.5 (347.0–418.0)429.0 ± 47.2 (356.0–494.0)451.3 ± 24.1 (420.0–473.0)0.941
Uric acid (mg/dL)4.9 ± 1.2 (3.3–6.5)3.8 ± 0.7 (3.3–4.9)4.4 ± 1.4 (0–3.0)4.3 ± 0.5 (3.9–5.0)0.303
Bile acids (μmol/L)36.9 ± 14.1 (18.0–62.0)50.5 ± 16.5 (29.0–68.0)34.3 ± 7.7 (27.0–47.0)54.0 ± 21.4 (30.0–82.0)0.013

Day 1 was the first day of administration.

Represents the comparison between the zonisamide-treated and control birds, when controlling for time; values were significant at P < 0.05.

ALP = Alkaline phosphatase. AST = Aspartate aminotransferase. CK = Creatine kinase. GDH = Glutamate dehydrogenase.

Discussion

In the study reported here, the pharmacokinetics of zonisamide, a commonly used AED in companion animal medicine, was evaluated in a psittacine species after administration of single or multiple doses. Results indicated that twice-daily oral gavage of zonisamide at a dose of 20 mg/kg over a 10-day period yielded plasma concentrations within a target range that would be considered therapeutic in dogs and humans and did not result in obvious signs of toxicoses.

The mean t1/2 for the single-dose trial (13.34 hours) was longer than that for the multiple-dose trial (9.76 hours). A potential cause for this difference would be hepatic enzyme autoinduction. Autoinduction has been reported for several AEDs in humans, but it has not been associated with zonisamide.18 In humans, zonisamide is metabolized by a combination of cytochrome P450 reduction, acetylation, and elimination of the unchanged parent drug in the urine.10 There currently are no data to indicate which metabolic pathway is responsible for clearance of zonisamide in avian species.

The mean Cmax reported for the multiple-dose trial (25.11 μg/mL) was higher than the Cmax for the single-dose trial (21.18 μg/mL) despite the fact a lower dose was administered during the multiple-dose trial. This finding was most likely attributable to the effect of accumulation. The t1/2 for the multiple-dose trial (9.76 hours) indicated that when zonisamide was readministered at 12-hour intervals, there were still therapeutic drug concentrations in the plasma. Accumulation is also supported by the relative bioavailability of 1.25 for the multiple-dose trial, compared with the single-dose trial, and a shorter MRT for the multiple-dose trial (13.81 hours) than for the single-dose trial (21.12 hours). Although accumulation led to an increase in Cmax, the parrot with the highest Cmax (28.3 μg/mL) had a concentration that was within the therapeutic range for humans and dogs (10 to 40 μg/mL)10,12,14 and did not cause toxicoses during the 10-day study. The Cmax for both trials was higher than that reported for chickens (14.8 ± 3.4 μg/mL) receiving zonisamide at a dosage of 20 mg/kg twice daily,a which indicates species differences in absorption and metabolism of zonisamide. Further studies are required to determine whether long-term administration of zonisamide would lead to increases in plasma concentrations of zonisamide and a higher potential for adverse effects. On the basis of these findings, it is recommended that clinicians perform periodic evaluations of plasma concentrations of zonisamide to ensure patient safety.

Mean Tmax for the single-dose trial (4.75 hours) was 2 times as great as the mean Tmax for the multiple-dose trial (2.25 hours). This difference may have stemmed from enzyme autoinduction and the effects of accumulation. The Tmax for the multiple-dose trial was similar to that reported for chickens.a

Although zonisamide is considered a safe medication for companion animals, several adverse effects have been noted in dogs and cats, including vomiting, diarrhea, ataxia, erythema multiforme, renal tubular acidosis, and idiosyncratic hepatic necrosis.19–22 In chickens, immune-mediated hemolytic anemia, severe hepatic necrosis, and dose-dependent diarrhea have been reported.a None of the parrots in the present study exhibited appreciable adverse effects during the 10-day treatment period, as determined on the basis of daily observation of mentation and evaluation of urofeces, serial measurements of body weight, and assessment of CBC and biochemical variables.

Birds treated with zonisamide in the present study had several hematologic and biochemical variables that differed significantly from values for control birds, when controlling for time. Control birds had a higher PCV and lower eosinophil count after 10 days. Differences in biochemical variables for zonisamide-treated birds, compared with results for control birds, were evident for electrolytes (sodium, potassium, chloride, and calcium) and bile acids. Despite the fact there were significant differences between groups, all hematologic and biochemical variables were within published reference values23 for this species or were clinically unimportant differences. On the basis of the lack of biochemical variables that were outside of published reference values as well as results of clinical evaluation of the birds during the study and for > 6 months after study completion, there was no evidence that repeated administration of zonisamide at the dose evaluated in this study (20 mg/kg, PO, q 12 h) over a 10-day period would lead to toxic effects. It is unknown whether a prolonged period of treatment would lead to more pronounced hematologic or biochemical abnormalities, and it is recommended that serial hematologic and biochemical analyses be performed for clinical monitoring of psittacine patients receiving long-term treatment with zonisamide.

The study reported here had several limitations. The period of administration (10 days) may not have been sufficient to enable us to detect toxic events that may have occurred during extended administration of AEDs over a more prolonged period for management of seizures. In the present study, we evaluated only 8 parrots that received multiple doses of zonisamide, and we did not evaluate the pharmacokinetics of this AED when administered concurrently with other AEDs such as levetiracetam and phenobarbital, which is often the case for the treatment of epilepsy. Finally, this study was a pharmacokinetic study and not a pharmacodynamic evaluation of the anticonvulsant effects of zonisamide. Although it is assumed that plasma concentrations known to be therapeutic in other species would have similar effects in Amazon parrots, this was not evaluated in the present study. Clinicians who administer zonisamide to epileptic parrots should be cognizant of the limitations of the study reported here.

For both the single- and multiple-dose trials reported here, concentrations of zonisamide were within the therapeutic target concentration reported for other species, and there were no appreciable adverse effects over the 10-day period. Although we did not evaluate pharmacodynamics in the present study, the pharmacokinetic results indicated that twice-daily oral administration of zonisamide at a dose of 20 mg/kg to Hispaniolan Amazon parrots would be a safe anticonvulsant option that may be effective for the treatment of seizures in this species. Differences between this species and chickens for the pharmacokinetics and toxicoses of zonisamide highlight the fact that it is challenging to make comparisons of dosages and pharmacokinetics across species. Serial monitoring of the CBC, plasma biochemical variables, and plasma concentrations of zonisamide is recommended to ensure safe and efficacious long-term treatment with this AED.

Acknowledgments

Supported by the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis.

The authors thank Dr. Tracy Drazenovich for technical assistance.

ABBREVIATIONS

AED

Antiepileptic drug

AUC

Area under the plasma concentration–time curve

Cmax

Maximum plasma concentration

MRT

Mean residence time

t1/2

Terminal half-life

Tmax

Time to maximum plasma concentration

Footnotes

a.

Noonan B, Boothe D, Morrisey J, et al. Pharmacokinetics of the anti-epilepsy drug zonisamide in domestic chickens (abstr), in Proceedings. 33rd Annu Meet Assoc Avian Vet 2012;329.

b.

ZuPreem FruitBlend Flavor, ZuPreem Nutritional Products Inc, Shawnee, Kan.

c.

Wockhardt USA LLC, Parsippany, NJ.

d.

Ora-Sweet, Paddock Labs Inc, Minneapolis, Minn.

e.

Ora-Plus, Paddock Labs Inc, Minneapolis, Minn.

f.

Microtainer, Becton Dickinson and Co, Franklin Lakes, NJ.

g.

Bio Plas Inc, San Rafael, Calif.

h.

Aerospray Stat, Wescor Inc, Logan, Utah.

i.

EMD Chemicals Inc, Gibbstown, NJ.

j.

Vetlab Supply, Palmetto Bay, Fla.

k.

Jorgensen Laboratories Inc, Loveland, Colo.

l.

Nebauer hemacytometer, Thomas Scientific, Swedesboro, NJ.

m.

Roche Cobas C311 chemistry analyzer, Diamond Diagnostics, Holliston, Mass.

n.

Zonisamide immunoassay, ARK Diagnostic, Sunnyvale, Calif.

o.

Dimension Xpand Plus, Siemens, New York, NY.

p.

ARK zonisamide calibrator, ARK Diagnostics Inc, Sunnyvale, Calif.

q.

ARK zonisamide control, ARK Diagnostics Inc, Sunnyvale, Calif.

r.

WinNonLin, Pharsight Corp, Mountain View, Calif.

s.

Stata/IC, version 12.1, StataCorp LP, College Station, Tex.

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