Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy

Abstract

RationaleBarriers to developing treatments for human status epilepticus include the inadequacy of experimental animal models. In contrast, naturally occurring canine epilepsy is similar to the human condition and can serve as a platform to translate research from rodents to humans. The objectives of this study were to characterize the pharmacokinetics of an intravenous (IV) dose of topiramate (TPM) in dogs with epilepsy and evaluate its effect on intracranial electroencephalographic (iEEG) features.MethodsFive dogs with naturally occurring epilepsy were used for this study. Three were getting at least one antiseizure drug as maintenance therapy including phenobarbital (PB). Four (ID 1–4) were used for the 10 mg/kg IV TPM + PO TPM study, and three (ID 3–5) were used for the 20 mg/kg IV TPM study. IV TPM was infused over 5 min at both doses. The animals were observed for vomiting, diarrhea, ataxia, and lethargy. Blood samples were collected at scheduled pre- and post-dose times. Plasma concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Non-compartmental and population compartmental modeling were performed (Phoenix WinNonLin and NLME) using plasma concentrations from all dogs in the study. iEEG was acquired in one dog. The difference between averaged iEEG energy levels at 15 min pre- and post-dose was assessed using a Kruskal–Wallis test.ResultsNo adverse events were noted. TPM concentration–time profiles were best fit by a two compartment model. PB co-administration was associated with a 5.6-fold greater clearance and a ~4-fold shorter elimination half-life. iEEG data showed that TPM produced a significant energy increase at frequencies >4 Hz across all 16 electrodes within 15 min of dosing. Simulations suggested that dogs on an enzyme inducer would require 25 mg/kg, while dogs on non-inducing drugs would need 20 mg/kg to attain the target concentration (20–30 μg/mL) at 30 min post-dose.ConclusionThis study shows that IV TPM has a relatively rapid onset of action, loading doses appear safe, and the presence of PB necessitates a higher dose to attain targeted concentrations. Consequently, it is a good candidate for further evaluation for treatment of seizure emergencies in dogs and people.

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

“…Over the past 15 years, several peer‐reviewed NLME analyses in veterinary pharmacology have been published. The most recent examples include the study of topiramate in epileptic dogs (Vuu et al., ); nonsteroidal anti‐inflammatory drug (NSAIDs) in dogs and cats with osteoarthritis (Cox, Liao, Payne‐Johnson, Zielinski, & Stegemann, ; Fink et al., ; Pelligand, Soubret, King, Elliott, & Mochel, ; Silber et al., ); tobramycin in horses (Haritova, Bakalov, Hubenov, & Lashev, ); valnemulin and cefquinome in pigs (Zhao et al., , ); tulathromycin in lactating goats (Lin, Cuneo et al., ; Lin, Gehring et al., ); and penicillin G in cattle and swine (Li et al., ).…”

Idiosyncratic reaction of topiramate in a Maine Coon cat

“…The canine pharmacology profile was investigated by Streeter et al 9 . and recently by Vuu et al 10 ,. which revealed appropriate clinical properties that can assist in developing future clinical trials.…”

“…It was evaluated as an add-on AED for refractory idiopathic epilepsy in dogs, 2 neuropathic pain in Chiari-like malformation, 6 and feline idiopathic ulcerative dermatitis. 7,8 The canine pharmacology profile was investigated by Streeter et al 9 and recently by Vuu et al 10 , which revealed appropriate clinical properties that can assist in developing future clinical trials. On an open-label clinical trial of topiramate in idiopathic epileptic seizures, 2 five of 10 dogs had more than 50% reduction in seizure frequency during the 2 months evaluation period.…”

Preparation and evaluation of bilayer-core osmotic pump tablets contained topiramate

“…the parameters related about drug elimination greatly. Therefore, the parameters of elimination half-life (~10 h) was longer the references reported (3.7-5 h) [37]. It was reported that the mean plasma elimination half-life was 19-23 h in healthy volunteers without enzyme induction.…”

“…It was reported the effective blood concentration of TPM in human with status epilepticus was 2-40 μg/mL [37]. Based on this, the blood drug concentration of PPOP tablets here might be unable to produce sufficient therapeutic effect in vivo.…”