The disposition and bioequivalence of single-dose compounded, commercial, and intravenous levetiracetam in healthy dogs

Epilepsy is among the most common chronic neurologic conditions in dogs and carries an increased risk of premature death due to owner perception of poor quality of life associated with inadequate seizure control and adverse medication effects. One cause of inadequate seizure control is poor adherence to medication schedules, which has been associated with more frequent dosing. Levetiracetam (LEV) is an anti-epileptic drug (AED) that is used extra-label in dogs and cats, where it has become popular due to its perceived efficacy, wide safety margin, mild adverse effect profile, suitability for use in patients with hepatic dysfunction, and potential synergy with AEDs that act by other mechanisms. LEV is available in two oral formulations, an immediate-release (LEV-IR) formulation administered three times daily and an extended-release formulation (LEV-ER) administered twice daily. Per manufacturer specification, the large LEV-ER tablets cannot be crushed or split, limiting its use in small dogs. A compounded formulation of LEV-ER (PO-COMP) manufactured by a licensed outsourcing facility operating under Section 503B of the Federal Food, Drug, and Cosmetics Act can purportedly be crushed or split without loss of extended-release properties. The goals of the present study were to (1) establish the pharmacokinetic parameters of partitioned PO-COMP, including absolute bioavailability relative to commercially available intravenous LEV (IV-COMM), and (2) determine the bioequivalence of partitioned PO-COMP to an intact commercially available oral generic formulation of LEV-ER (PO-COMM) in healthy dogs. We hypothesized that pharmacokinetic parameters of partitioned PO-COMP would be similar to intact PO-COMM and appropriate for twice daily dosing in dogs with high absolute bioavailability, and that partitioned PO-COMP would be bioequivalent to intact PO-COMM. Twelve healthy dogs, no less than 12 months old and weighing at least 15 kilograms, were prospectively enrolled in a randomized crossover study, and received a single IV dose of IV-COMM (30 mg/kg), a single oral dose of PO-COMM (500 mg, intact tablet) or a single oral dose of PO-COMP (500 mg, partitioned tablet). Samples were collected at prescribed timepoints during the 24 h after administration, with the other formulations given following a washout period. Serum levels were quantified using a validated immunoassay. Pharmacokinetic analysis for IV-COMM, PO-COMM, and PO-COMP were performed using non-compartmental methods. The absolute bioavailability of PO-COMP and PO-COMM were calculated by the area under the curve (AUC) method. PO-COMM and PO-COMP were considered bioequivalent if the 90% confidence interval (CI) fell within ± 20% for maximum serum concentration (Cmax) and AUC. The absolute bioavailability of PO-COMP was 78 ± 19% and PO-COMM was 95 ± 15%. The geometric mean of the difference between PO-COMM and PO-COMP in Cmax was -0.56 mcg/mL (-3.2% relative to PO-COMM) (90% CI: -7.4%, +1.1%) and AUC was -22 mcg*h/mL (-14.4% relative to PO-COMM) (90% CI: -17.8%, -10.8%). Based on a target CI of ± 20% for both parameters, the treatments were considered bioequivalent. The absolute bioavailability of partitioned PO-COMP is similar to that of intact PO-COMM, as published elsewhere. Partitioned PO-COMP and intact PO-COMM are bioequivalent, suggesting that partitionable PO-COMP may be a viable treatment option in small breed epileptic dogs who cannot receive intact PO-COMM due to large tablet size or tendency to damage the tablet during ingestion, and may improve medication adherence relative to LEV-IR, which requires three times daily dosing.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

VMS-Veterinary Clinical Medcne

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Paushter, Aaron Michael

Contributors dc:contributor

• Foss, Kari D
• Reinhart, Jennifer
• Forsythe, Lauren
• Hague, Devon

• Canine Epilepsy
• Keppra Extended Release
• Levetiracetam Extended Release
• Compounded Medication

Statement dc:rights

• Copyright 2024 Aaron Michael Paushter

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/124545

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F124545