Intravenous topiramate for seizure emergencies – First in human case report

Apostolakopoulou, Loukia; Varela, Pilar Bosque; Rossini, Fabio; O’Sullivan, Ciara K.; Löscher, Wolfgang; Kuchukhidze, Giorgi; Trinka, Eugen

doi:10.1016/j.yebeh.2023.109158

Cited by 4 publications

(2 citation statements)

References 12 publications

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“…This expectation is substantiated by a recent case report in which the meglumine‐based TPM solution was well tolerated following i.v. administration in a patient with epilepsy 59 . The planned development path of the novel meglumine‐based TPM solution will include (1) the evaluation of the efficacy of different i.v.…”

Section: Discussionmentioning

confidence: 99%

“…administration in a patient with epilepsy. 59 The planned development path of the novel meglumine-based TPM solution will include (1) the evaluation of the efficacy of different i.v. doses of TPM to terminate established SE in the pilocarpine rat model, using LEV as a reference drug; (2) the determination of plasma and brain pharmacokinetics of effective doses of i.v.…”

Section: Further Development Of the Meglumine-based Solution Of Topir...mentioning

confidence: 99%

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Preclinical pharmacokinetics and tolerability of a novel meglumine‐based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus

Rundfeldt¹,

Klein

Boison

et al. 2023

Epilepsia

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Objective: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy-to-use and easy-to-prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)-approved excipient meglumine. Methods:During formulation development, we compared the solubility of TPM in bi-distilled water with vs without a range of meglumine concentrations.Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine-based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine-induced SE. Results:The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether-βcyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co-administered with another ASM for SE treatment. The tolerability studies of the meglumine-based TPM solution and meglumine-based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpineinduced SE models demonstrate excellent tolerability of the novel drug solutions.Preclinical studies on antiseizure efficacy in the SE model are underway.

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Section: Discussionmentioning

confidence: 99%

Section: Further Development Of the Meglumine-based Solution Of Topir...mentioning

confidence: 99%