The pharmacokinetics of single oral dose extended-release topiramate and adverse effects after multi-dose administration in healthy cats

Graham, Lindsey T.

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https://hdl.handle.net/2142/120430 Copy

Description

Title

The pharmacokinetics of single oral dose extended-release topiramate and adverse effects after multi-dose administration in healthy cats

Author(s)

Graham, Lindsey T.

Issue Date

2023-05-02

Director of Research (if dissertation) or Advisor (if thesis)

Foss, Kari

Committee Member(s)

• Hague, Devon
• Smith, Kathryn
• Reinhart, Jennifer

Department of Study

Vet Clinical Medicine

Discipline

VMS-Veterinary Clinical Medcne

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

M.S.

Degree Level

Thesis

Keyword(s)

• Feline
• seizures
• epilepsy
• antiseizure
• glaucoma

Abstract

Epilepsy is a common neurologic disorder in feline patients, with an estimated prevalence of 0.5-3% in cats presenting to referral hospitals. Starting antiepileptic drugs (AEDs) is often recommended, especially in cats with frequent or prolonged seizure activity. Current treatment options for feline epilepsy are limited to medications that require administration of multiple doses per day, or administration of a large pill. Expanding the current treatment options could improve patient and owner compliance and optimize seizure control. Topiramate is a broad spectrum, second-generation anticonvulsant available for the treatment of partial onset and generalized tonic-clonic seizures in the United States since 1996. Since topiramate’s initial development, two extended-release formulations have been manufactured (Trokendi XR® and Qudexy®). Qudexy® (QXR) has a unique feature of being manufactured in capsules, which can be opened and sprinkled directly onto food to facilitate administration in humans. Topiramate has been used sparingly in veterinary medicine and limited pharmacokinetic studies have focused on immediate release formulations in dogs. If effective and safe, topiramate extended-release (XR) could broaden the current treatment options for feline epilepsy. The aims of this two-phase study were (i) to establish single dose pharmacokinetics for topiramate XR in cats and identify a dosing regimen that maintains steady state plasma drug concentrations within a therapeutic range extrapolated from human medicine; and (ii) to evaluate the safety of topiramate XR in cats following multidose administration over a 30-day period. We hypothesized that once daily administration of topiramate XR would lead to plasma drug concentrations maintained within 5-20 µg/mL at steady state throughout the dosing interval. Additionally, we hypothesized multidose administration of topiramate XR would be safe and well-tolerated in cats. Eight, healthy staff-owned cats were enrolled in the study. Inclusion criteria included an age of > 1 year, a weight of > 3.7 kg, and absence of systemic illness. Baseline physical, neurologic, and ophthalmic examinations and a minimum database were performed prior to the start of phase 1. Cats were assigned to receive either a single 5 mg/kg or 10 mg/kg oral dose of topiramate XR. Plasma topiramate concentrations were determined using liquid chromatography-mass spectrometry and steady state predictions made for once and twice daily oral administration for both the 5 mg/kg and 10 mg/kg dosing. Predicted plasma concentrations were compared to a therapeutic range extrapolated from human medicine (5-20 µg/mL) to determine a dosage and frequency that would be expected to fall within the therapeutic topiramate concentration range established in humans. Steady state predictions revealed that 10 mg/kg administered once daily and 5 mg/kg administered twice daily were expected to achieve the desired concentration range. Given the limited once daily AED options available for cats, the 10 mg/kg once daily dose was selected for evaluation during phase 2. The eight cats from phase 1 were then administered 10 mg/kg of topiramate XR sprinkled on food once daily for 30 days. During this second phase, weekly vital parameters and intraocular pressure (IOP) were measured. Immediately prior to administration of the final dose on day 30, a baseline plasma sample was obtained. Samples were then obtained every 6 hours for 24-hours post-administration. The samples were analyzed using the same method as in phase 1. The study demonstrated topiramate XR administered orally at 10 mg/kg once daily for 30 days was sufficient to achieve the desired plasma concentrations in all cats. While no clinically apparent adverse effects were observed, 4 out of 8 cats developed subclinical anemia, calling into question the safety of topiramate XR with chronic administration at this dosage. Further studies are necessary to better understand the potential adverse effects and overall efficacy of topiramate XR for the treatment of feline epilepsy.

Graduation Semester

2023-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Lindsey Graham

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