Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs

Abstract

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady-state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross-over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one-way anova; P </= 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C(max) was 14.4 +/- 2.3 mcg/mL and elimination half-life was 17.2 +/- 3.6 h. After IV dosing, volume of distribution was 1.1 +/- 0.25 L/kg, clearance was 58 +/- 11 mL/h/kg and elimination t(1/2) was 12.9 +/- 3.6 h. Oral bioavailability was 68 +/- 12%; fraction of unbound drug approximated 60%. At steady-state (4 days), differences occurred for for all parameters except C(max) and C(min.) Plasma C(max) at steady-state was 56 +/- 12 mcg/mL, with 10% fluctuation between C(max) and C(min.) Plasma t(1/2) (h) was 23.52 +/- 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 microg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.