The purpose of this study was to design a dosing regimen and evaluate the safety of zonisamide (ZNS) following multiple dosing and to determine appropriate monitoring methods. Clinical pharmacokinetics were studied in 8 adult dogs (4 male and 4 female) ranging from 3 to 4 years of age using a randomized crossover design following single intravenous (IV) and oral administration, 6.85 and 10.25 mg/kg, respectively. Samples were collected intermittently for 48 hours. Dogs were then dosed orally (10.17 mg/kg) twice daily for 8 weeks. Blood samples were collected weekly and at discontinuation of the drug. Additionally, urine was collected to determine 24 hour urine ZNS clearance following IV administration. Safety was based on clinical pathology, thyroid and urine testing during both studies.
ZNS was measured using high performance liquid chromatography in serum, plasma, erythrocytes (RBC) and whole blood. Data were subjected to standard non-compartmental pharmacokinetic analysis using computer assisted linear regression (WinNonLin?). Comparisons were made in different compartments using one-way ANOVA to identify any differences. Safety parameters at study beginning and end were compared using a Student t-test.
ZNS concentrations differed among blood compartments after single dosing, with oral maximum concentration (Cmax) being greatest in RBC (28.73?g/ml) and least (14.36?g/ml) in plasma. Volume of distribution also differed, being greater (1096.05ml/kg) in plasma and least in (379.23ml/kg) RBC. Clearance of ZNS was 57.55ml/hr/kg from plasma and 5.06ml/hr/kg from RBC. Elimination half- life in plasma was 16.4 hr in serum and 57.4 hr in RBC. Bioavailability was 126.8% for RBC and 189.6% for plasma.
Following multiple dosing, at steady-state, Cmax averaged 65.8?g/ml with fluctuations of 17.2% between dosings. Accumulation of ZNS was 3.5 (plasma) and 4.3 (RBC). Concentrations did not differ among blood compartments at the end of multiple dosing. Although differences did occur across time in clinical pathology tests, all were within normal limits at study end except for T4.
In conclusion, ZNS dosed at 10 mg/kg twice daily for dogs would maintain therapeutic levels (10 to 70?g/ml) recommended in human epileptic patients. Therapeutic monitoring would be best measured in serum or plasma accompanied with thyroid and urine testing.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/1127 |
| Date | 15 November 2004 |
| Creators | Perkins, Jeremy Dane |
| Contributors | Boothe, Dawn, Kochevar, Deborah |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Thesis, text |
| Format | 354610 bytes, 96165 bytes, electronic, application/pdf, text/plain, born digital |
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